Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning Academic research paper on "Basic medicine"

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Neuropharmacology

journal homepage: www.elsevier.com/locate/neuropharm

Invited review

Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning

Sreedeep Mukherjeea,b, Denise Manahan-Vaughan

a, b, *

a Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, 44780 Bochum, Germany b International Graduate School of Neuroscience, Ruhr University Bochum, 44780 Bochum, Germany

ARTICLE INFO

Article history: Received 21 March 2012 Received in revised form 31 May 2012 Accepted 1 June 2012

Keywords:

Learning

Long-term memory Hippocampus In vivo Review

ABSTRACT

Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampus-dependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events.

This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

© 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Glutamate is one of the most important excitatory neurotransmitters in the central nervous system (CNS) and plays an important role in various integrative brain functions, as well as in brain development. Glutamate generally mediates fast excitatory transmission across the nervous system. This effect is enabled by fast-acting ligand-gated ionotropic glutamate (iGlu) receptor channels, namely the N-methyl-D-aspartate (NMDA) receptors, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and Kainate iGlu receptors. Glutamate also acts through more slowly activating G-protein-bound receptors, which act via 2nd messenger systems. These glutamatergic receptors modulate cellular excitability and synaptic transmission and are referred to as metabotropic glutamate (mGlu) receptors. They exhibit a widespread distribution in the CNS and play a major role in various neuronal processes including synaptic plasticity and memory formation.

* Corresponding author. Department of Neurophysiology, Medical Faculty, Ruhr University Bochum, Universitaetsstr. 150, MA 4/150, 44780 Bochum, Germany. Tel.: +49 234 32 22042; fax: +49 234 32 14490.

E-mail address: denise.manahan-vaughan@rub.de (D. Manahan-Vaughan).

0028-3908/$ - see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuropharm.2012.06.005

1.1. Subtypes of mGlu receptors

The very first description of mGlu receptors occurred when two different labs cloned and isolated the first mGlu receptor encoding cDNA (Houamed et al., 1991; Masu et al., 1991) termed mGlu1a. Analysis of the amino acid sequence of the first mGlu receptor revealed a quite distinct identity of the receptor from iGlu receptors, owing to their large extracellular N-terminal domain, a seven transmembrane domain and a large C-terminal domain. By screening several cDNA libraries using mGlu1a sequence as a probe, scientists isolated eight other genes and several splice variants that encode mGlu receptors to date (Tanabe et al., 1992; Pin et al., 1992; Abe et al., 1992; Nakajima et al., 1992; Okamoto et al., 1994; Saugstad et al., 1994; Joly et al., 1995,1995; Minakami et al., 1994; Minakami et al., 1994; Duvoisin et al., 1995; Iversen et al., 1994; Laurie et al., 1996, 1997). Amino acid sequencing of mGlu receptors reveal no sequence homology with other G-protein coupled receptors, suggesting that the mGlu receptors comprise a new receptor gene family. Along with Ca2+-sensing receptors, putative pheromone receptors and GABAB receptors (Bockaert and Pin, 1999), mGlu receptors are a member of the family 3 of G -protein -coupled receptors (GPCRs).

Mainly based on their sequence similarity, but also on their transduction mechanisms and pharmacological properties, mGlu

receptors have been classified into 3 groups (Pin and Duvoisin, 1995; Nakanishi, 1994) (Table 1). Intra-group sequence similarity is about 60—70%, whereas by comparing between groups the similarity falls to 40—45%. Group I mGlu receptors comprise mGlul and mGlu5, which activate Gq proteins, whereas group II and group III mGlu receptors are coupled to pertussis toxin sensitive G-proteins, and comprise mGlu2, 3 (group II) and mGlu 4, 6, 7 and 8 (group III).

1.2. Splice variations

With the exception of mGlu2, splice variants have been identified for all mGlu receptors (Table 1). Six distinct types of C-terminal splice variants have been reported for the mGlul gene (Hermans and Challiss, 2001), namely mGlula, lb, lc, ld, le and lf of which the longest is mGlula (Pin and Duvoisin, 1995; Soloviev et al., 1999; Hermans and Challiss, 2001). MGlu5 exists as two main isoforms, mGlu5a and mGlu5b (Joly et al., 1995). Other isoforms such as mGlu5c, 5d and 5e have been reported in humans (Minakami et al., 1994).

Exon-skipping events lead to three spliced variants in mGlu3 (Sartorius et al., 2006). For group III receptors, mGlu4 exists as mGlu4a, and mGlu4b (Thomsen et al., 1997). Three mGlu6 isoforms have been reported. One mGlu6b in rat retina forms a 508 amino acid truncated protein due to insertion of an in frame stop codon. Human retina has two isoforms, hmGlu6b and hmGlu6c, consisting of 425 and 405 amino acids. Both rat and human protein lack the TM and intracellular portions, thus are secreted and might act as soluble glutamate receptors or as a dominant negative receptor variant (Valerio et al., 2001). MGlu7 and 8 isoforms have been

identified from rat brain (Corti et al., 1998). MGlu7 forms five C terminal-end isoforms: mGlu7a to mGlu7e (Niswender and Conn, 2010). MGlu8 reported forms three isoforms, mGlu8a—c and 8b (Pin and Duvoisin, 1995; Malherbe et al., 1999). The splicing site in mGlu7 is analogous to mGlul, 4 and 5 (Corti et al., 1998); showing conservation of this site in many mGlu receptor genes (Conn and Pin, 1997).

1.3. Pharmacological properties

The pharmacology of the mGlu receptors is mainly based on two types of distinctly acting ligands. The classical competitive ligands exert clear agonist and antagonist effects, acting via the orthosteric ligand binding site in the N-terminal domain (Table 1). The other type consists of the emerging class of non-competitive ligands, comprising various allosteric modulators that bind the transmembrane domain of mGlus (Table 1). Many of the competitive ligands, which mostly comprise constrained or substituted amino acid analogues, have greatly enabled the study of various effects of mGlus. But their utility is limited due to their limited CNS bioavailability and poor pharmacokinetic properties. Also the evolutionary-conserved structure of the ligand-binding domain has hindered the identification of individually-selective competitive mGlu ligands. This has been overcome by usage of the non-competitive ligands, that have better selectivity and bioavail-ability. A very detailed overview of the pharmacological properties of metabotropic glutamate receptors is beyond the scope of this review, and has been extensively reviewed elsewhere (Niswender and Conn, 2010; Pin and Acher, 2002; Conn and Pin, 1997; Kew and Kemp, 2005).

Table 1

Table provides an overview of the cellular localization, hippocampal distribution, signaling pathways and G-protein coupling of the mGlu receptors.

Group Subtype Cellular localisation Hippocampal distribution Signalling pathways and G-protein coupling

I mGlul Mainly postsynaptic, Cell layers of the CA1 and the Gq-coupled:c Stimulates PLC.

also present on dendritic fields of the CA3 and DG. Increases DAG and 1P3 and intracellular Ca2+

interneuronesa (mGlula on interneurones, mGlulb on CA3 pyramidal neurones, & on DG granule cells)b

mGlu5 Mainly postsynaptic, also present on interneuronesd,e.f.g dendritic fields of CA1 neurons, as well as DG (strong expression) and CA3h

II mGlu2 Mainly presynaptici pre-synaptic boutons of the mossy fibres and the perforant pathi Gi/Go-coupled:1nhibits adenylyl cyclase; decreases cAMP and intracellular Ca2+;

mGlu3 Neurones (mainly presynaptically) and astrocytesj,k Molecular layer of dentate gyrus, entorhinal and subicular cortexl act as autoreceptors for glutamate

III mGlu4 Mainly presynaptick CAl-CA3 regions (albeit low expression)i Gi/Go-coupled: Inhibit adenylyl cyclasem;

mGlu6 Postsynapticn Only found in retina" decrease cAMP and cGMP and intracellular Ca2+;

mGlu7 Presynaptico CA1 and DG; active zones of presynaptic terminalso act as auto—receptors for glutamateq.

mGlu8 Presynapticp Colocalises with mGlu7, also found on perforant path terminalsp

Abbreviations: cyclic adenosine monophosphate (cAMP); cyclic guanosine monophosphate (cGMP); dentate gyrus (DG); diacyl glycerol (DAG); inositol trisphosphate (IP3) phospholipase C (PLC). a Ferraguti et al., 1998. b Mateos et al.,1998. c Pin and Duvoisin 1995. d Shigemoto et al., 1995. e Takumi et al., 1999. f Kerneretal., 1997. g Baude etal., 1993.

h Lujan et al., 1996, 1997.: Hanson and Smith, 1999. i Ferraguti and Shigemoto, 2006. j Ohishi et al., 1993. k Tanabe et al.,1993. ' Tamaruetal., 2001. m Conn and Pin, 1997. n Nomura etal., 1994. o Okamoto et al., 1994. p Corti et al., 1998. q Maceketal., 1996.

1.4. Signal transduction mechanisms

The proteins of the GPCR family comprise constitutive dimers and include the mGlu receptors. Generally, activation mechanisms of mGlu receptors follow three basic steps: a) binding of competitive agonists to the venus flytrap domain (VFD) closes and stabilizes it, b) the closed VFD transduces the signal via the Cysteine rich domain(CRD) and c) activation of the G-protein (Pin et al., 2004; Tsuchiya et al., 2002).

Antagonists inhibit receptor activation by inhibiting the closure of the VFD (Pin et al., 2004; Tsuchiya et al., 2002). Studies using GPCR chimeras have shown that although closure of one binding domain is sufficient for activation, the closed state of both binding domains leads to full agonist activity (Kniazeff et al., 2004). Thus, VFD closure is necessary for activation. VFD closure, upon agonist binding, induces both VFDs within the dimer to undergo a rotation which helps in propagating the activation throughout the protein (Pin et al., 2004). A recent study using a mutated mGlu5 dimer showed that inter-subunit rearrangement within the VFD plays a crucial role for activation of mGlu receptors (Brock et al., 2007).

Group I mGlu receptors are primarily coupled to Gq/Gll proteins and secondarily coupled to Gs and pertusis toxin-sensitive Go. Activation of these receptors leads to phosphatidyl inositol (PI) hydrolysis by activating phospholipase C (PLC) with resultant formation of mainly two 2nd messengers, inositol 1,4,5-tri-sphosphate (1P3) and diacylglycerol (DAG). The former enhances intracellular Ca2+ release, whereas the latter results in activation of protein kinase C (PKC). Activated group 1 mGlus activate a plethora of downstream effector molecules such as phospholipase D, cyclic adenosine mono phosphate (cAMP) formation, arachidonic acid release, the mitogen activated protein kinase (MAPK) pathway and the phosphatidylinositol kinase (P13K) pathway, as well as others dependent on cell types and the specific neuronal population (Niswender and Conn, 2011; for review see Conn and Acher, 2002; Conn and Pin, 1997). Activation of the MAPK/ERK pathway and the mammalian target of rapamycin (mT0TR)/p70S6 kinase by group 1 mGlu receptors has been especially implicated in synaptic plasticity (Page et al., 2006; Hou and Klann, 2004). G-protein independent cascades involving Src-like protein kinases have been also reported for group 1 mGlu receptors (Heuss et al., 1999). In the case of group 11 and 111 mGlu receptors, both are coupled to Gi/Go type of G-proteins. Such a coupling primarily results in inhibition of ade-nylyl cyclase and modulation of ion channel activity, presumably mediated by ßg subunit of the coupled G-protein. Activation of the MAPK and P13 kinase pathways by group 11 and 111 receptors have also been reported (1acovelli et al., 2002), as has mGlu-mediated amplification of cAMP stimulation by ß-adrenergic agonist in cultured astrocytes (Nicoletti et al., 2009). These findings further enhance the complexity regarding the role of these receptors in affecting synaptic transmission.

1.5. Protein—protein interaction

G-protein independent regulation of cellular processes by mGlu receptors is mainly performed by interacting with other proteins mediated by the C-terminal end of each of the mGlu subtypes. Many of the interactions serve particular functions such as: a) targeting the receptor to specific site, b) anchoring the receptors, c) maintenance of proximal distance between signalling partners, and d) functional regulation of mGlu signalling. Homer 1a was identified as one of the earliest mGlu binding partners, isolated from rat hippocampus following LTP by means of differential cloning (Brakeman et al., 1997; Kato et al., 1997). Homer 1a is expressed only during brain development or during cortical activity whereas the other isoforms, Homer-1b/c, Homer-2a/band Homer-3, are

constitutively expressed. All homer protein isoforms contain an N terminal EVH1 domain and a C-terminal coiled-coil domain, with the exception of Homer-1a that lacks the coiled coil domain, and is thus categorized as a short homer variant, (the others are referred to as long variants). A proline-rich consensus sequence (PPxxFR), present at the C-terminal domain of mGlu1a and mGlu5a/b interacts with the EVH1 domain of homer isoforms. Apart from associating long forms of mGlu with other proteins into the post- synaptic element (Husi et al., 2000), this interaction also leads to mGlu targeting to different subcellular compartments, membrane insertion and glutamate-independent activation of the receptor (Ango et al., 2001, 2000, 2002). P1CK1 (protein interacting with C kinase 1) interacts with the C-terminal domain of mGlu7 and with PKCa (Staudinger et al., 1997), via a coiled coil domain, and co-localizes both in hippocampal cell cultures (Enz, 2007) and in active zones of presynaptic terminals (El Far and Betz, 2002). 1t does not target these proteins to presynaptic sites, however (Boudin et al., 2000; Boudin and Craig, 2001). MGlu1a and mGlu5 both interact with tamalin: the former interaction leads to cell surface expression of the receptor and the latter leads to receptor targeting to neurites in hippocampal cultures (Kitano et al., 2002). GRK2 interacts with a short stretch of five amino acids located at the 2nd intracellular loop connecting Tm3 and 4 of mGlu1a and 1b and thus modulates their activity (Dhami et al., 2005). The protein phosphatase catalytic isoform, PP1g1, interacts with the C-terminal domain of mGlu7b but not 7a and with the C-terminal domains of mGlu1a and mGlu5 isoforms (Enz, 2002; Croci et al., 2003), whereas the PP2a isoform of protein phosphatase 2 interacts with the C terminus of mGlu3 (Flajolet et al., 2003; Enz, 2007). The C-terminal tails of mGlu1a, mGlu5 and mGlu7 interact with calmodulin (CaM) in a Ca2+ dependent manner. CaM-binding to these receptors is expected to affect or even prevent G-protein coupling and may regulate their transduction mechanisms (Pin and Acher, 2002). Mammalian homologues of Drosophila Siah-1A interact with the C-terminal tail of mGlu1a and nGlu5 (Ishikawa et al., 1999). In addition, a proximal sequence of mGlu7 C-terminus region interacts with alpha-tubulin and this sequence is conserved in all group 3 mGlus (Saugstad et al., 2002), whereas beta-tubulin interacts with C-terminal residues of mGlu1a (Ciruela et al., 1999). The above-mentioned details are intended as an overview, however this topic has recently reviewed in greater detail elsewhere (Enz, 200 , 2012; Pin and Acher, 2002; Bockaert et al., 2010).

1.6. Synaptic localizations and area-specific distribution

An overlapping distribution pattern of mRNA and immunore-activity for eight mGlu subtypes has been found in the brains of both rodents and primates. Extensive distributions of mGlu1, mGlu 3, mGlu 5 and mGlu 7 have been reported throughout the brain. By contrast, mGlu2, mGlu4 and mGlu8 have a region-restricted expression pattern, whereas mGlu6 is only found in retina. mGlu receptors are extensively expressed in neuronal cells but some are also expressed in glial cells (Ferraguti and Shigemoto, 2006).

1.6.1. Group I mGlu receptors

MGlu1 immunoreactivity is extensively found in the CNS, cerebellar cortex and olfactory bulb (Martin et al., 1992; Shigemoto et al., 1992). With regard to the hippocampus, mGlu1a is found mainly in hippocampal interneurons, whereas mGlu1b is expressed in CA3 pyramidal neurones, in the dentate gyrus granule cell layer and in the lateral hippocampus (Ferraguti et al., 1998; Mateos et al., 1998). MGlu5 is mainly localized to somatic and dendritic regions of the hippocampus, where it occurs in membrane domains peripheral to postsynaptic specialisations (Lujan et al., 1996,1997; Hanson and Smith, 1999, Romano et al, 1999), and is particularly

prominent in pyramidal and granule cells, as well as in GABAergic interneurons (Koerner et al., 1997). This receptor is mainly post-synaptically localised (Shigemoto et al., 1995; Takumi et al., 1999) although presynaptic localisation has also been described (Sistiaga et al., 1998; Manahan-Vaughan and Braunewell, 1999). The dentate gyrus is the hippocampal subregion with the highest mGlu5 expression, where receptors are localised to distal dendritic compartments of the dentate gyrus molecular layer and to inter-neurons (Baude et al., 1993; Lujan et al., 1996; Blumcke et al., 1996).

1.6.2. Group II mGlu receptors

MGlu2 is limitedly distributed in the Golgi cells of cerebellar cortex (Ohishi et al., 1993, 1994) and presynaptic structures of mossy fibres and perforant path (Ferraguti and Shigemoto, 2006). Whereas mGlu2 is present only on neurones, mGlu3 is found on both glial cells and neurones (Ohishi et al., 1993; Tanabe et al., 1993; Ghose et al., 1997). MGlu3 expression is extensive throughout the CNS, and receptors are localized in both pre- and post-synaptic regions of cerebral cortex and hippocampus (Tamaru et al., 2001). Group II receptors are predominantly presynaptically localised and, by means of their negative coupling to adenylyl cyclase, can strongly regulate presynaptic glutamatergic regulation and gluta-matergic excitability (Tanabe et al., 1992,1993; Lujan et al., 1997; Dietrich et al., 2002 ; Losonczy et al., 2003 ; Cahusac and Wan, 2007). In line with this, they are particularly important for the maintenance of low transmitter release probability at mossy fibre-CA3 synapses (Yoshino et al., 1996; Scanziani et al., 1997). As is the case with group I mGlu receptors their neuronal localisation is restricted to perisynaptic regions (Lujan et al., 1997).

1.6.3. Group III mGlu receptors

With regard to the group III receptors, only mGlu 4 and mGlu 7 are expressed in the hippocampus, with mGlu4 expression being comparatively low (Tanabe et al., 1993; Nakajima et al., 1993; Okamoto et al., 1994; Saugstad et al., 1994, 1997; Duvoisin et al.,

1995). MGlu8 influences hippocampal function, but this presumably occurs mainly via its presynaptic localisation on the terminals of the perforant path (Corti et al., 1998). The distribution of mGlu7 in the CNS is more extensive than its partner receptors, whereas mGlu6 is restricted to the post-synaptic part of the rod cells (Nomura et al., 1994). Intense expression of mGlu4 is found in the entorhinal cortex, the hippocampal CA1-3, hilus region (Shigemoto et al, 1997; Ferraguti and Shigemoto, 2006), in stratum lacunosum moleculare and stratum oriens and also on interneurons show immunoreactivity for mGlu4 (Corti et al., 2002; Kogo et al., 2004). Both mGlu7a and 7b are presynaptically localised, but 7a is mainly expressed throughout the dendritic layers of the hippocampus whereas mGlu7b is found in the terminal zones of the mossy fibres (Ferraguti and Shigemoto, 2006). Due to their presynaptic localisation, the group III mGlu receptors are referred to as autor-eceptors for glutamate, as they regulate presynaptic glutamate release and associated postsynaptic activity (Koerner and Cotman, 1981; Gereau and Conn, 1995; Macek et al., 1996).

2. Persistent forms of synaptic plasticity

Two main forms of hippocampal synaptic plasticity have been identified that persist for very long periods. Long-term potentiation (LTP) has been followed for up to one year in adult rodents (Abraham et al., 2002), whereas LTD that persists for at least 7 days has also been reported (Manahan-Vaughan et al, 1998, 1999). Whereas the longevity of both LTP and LTD in vitro has been demonstrated (Frey and Morris, 1997,1998; Frey, 2001; Frey et al.,

1996), it is rare that studies have been conducted in the hippo-campal slice preparation that investigate the role of mGlu receptors

for time-periods longer than 60 min after induction of synaptic plasticity. This has led to controversy about the role of mGlu receptors in both LTP and LTD. However, some studies have addressed the contribution of mGlu receptors to synaptic plasticity in the slice preparation, where effects were monitored over a period of hours (Neyman and Manahan-Vaughan, 2008; Wilsch et al., 1998). These data confirm observations that are detailed below, as to the contribution of mGlu receptors to persistent forms of plasticity in vivo (for overview, see Table 2).

In the hippocampus, both LTP and LTD occur in both NMDA receptor dependent (Coan and Collingridge, 1987; Collingridge et al., 1983a,b; Errington et al., 1987; Morris et al., 1990; Kameyama et al., 1998; Morishita et al., 2001; Collingridge et al., 2004) and independent forms (Massey and Bashir, 2007; Palmer et al., 1997; Johnston et al., 1992; Lopez-Garcia, 1998; Manabe, 1997; Manahan-Vaughan, 1997). In prenatal or early postnatal rodents, a differentiation between the NMDA-receptor-dependency and the mGlu receptor —dependency of LTP and LTD has been reported (Nosyreva and Huber, 2005; Ayala et al., 2008; Durand et al., 1996; Collingridge and Bliss, 1987). In adult rodents, this functional division of labour is not apparent. Typically, the induction phase of synaptic plasticity requires activation of NMDA receptors (Dudek and Bear, 1992; Bear and Malenka, 1994; Hrabetova and Sacktor, 1997; Manahan-Vaughan, 1997; Hrabetova et al., 2000; Raymond et al., 2000) or voltage-gated calcium channels (Grover and Teyler, 1990,1995; Blair et al., 2001 ; Aniksztejn and Ben Ari, 1991), whereas the maintenance phase of plasticity critically depends on the activation of mGlu receptors (Manahan-Vaughan, 1997, 2000; Klausnitzer et al., 2004; Pöschel and Manahan-Vaughan, 2005; Altinbilek and Manahan-Vaughan, 2007, 2008; Bikbaev et al., 2008).

2.1. Role of group I mGlu receptors in persistent LTP

Earlier work using less specific mGlu ligands revealed that both NMDA- and voltage-gated calcium channel-dependent LTP (>24 h) in the dentate gyrus and CA1 regions of the hippocampus require activation of group I but not group II mGlu receptors (Manahan-Vaughan et al., 1998). Many studies support that group I mGlus play a critical role in LTP that lasts for over 24 h (Balschun et al., 1999 ; Manahan-Vaughan, 1997; Naie and Manahan-Vaughan, 2004, 2005). More recent studies revealed a differential regulation by mGlu1 and mGlu5. Whereas mGlu1 was found to be involved in induction but not maintenance of persistent LTP, mGlu5 plays a significant role in the protein synthesis-dependent phase of LTP (Naie and Manahan-Vaughan, 2005, 2004; Balschun and Wetzel, 2002).

With regard to hippocampal LTP, chemical forms have been described that are induced by sole activation of mGlu receptors, in the absence of patterned afferent stimulation. Initial studies were conducted in vitro and showed how the group I and II mGlu agonist, 1-amino-1,3-dicarboxycyclopentane (1S,3R ACPD), induces slow-onset potentiation in the CA1 area of rat hippocampus (Bashir et al., 1993; Chinestra et al., 1994; Bortolotto and Collingridge, 1995). Later, this phenomenon was also demonstrated in vivo, where effects endured for over 4 h (Manahan-Vaughan and Reymann, 1995) and were prevented by an antagonist of group I mGlus (Manahan-Vaughan and Reymann, 1997). It is, however, not clear how physiological mGlu-mediated slow-onset potentiation is, as it causes cell death in the hippocampus (Manahan-Vaughan et al., 1999).

2.1.1. mGlul in persistent LTP

Activation of mGlu1 receptors triggers increases in intracellular calcium concentrations, depolarisation of pyramidal neurones in the CA1 region and an elevation in the frequency of spontaneous inhibitory post-synaptic potentials (Mannaioni et al., 2001). This

Table 2

Table provides an overview of the influence of mGlu receptors on persistent (>4 h) hippocampal long-term potentiation and long-term depression.

Group Subtype LTP LTD

I mGlul Antagonists impair CA1 & DG persistent LTP by reducing inductiona,b; Knockouts: impaired CA1 LTP, impaired mf LTPc,d Antagonists impair LTD by reducing induction & thereby preventing maintenance in CA1 & DGe,f; Knockouts: normal CA1 LTDc

mGlu5 Agonists facilitate STP into persistent (>24 h) LTPg; Antagonists reduce induction and prevent maintenance in CA1 & DGb; Knockouts: impaired CA1& DG LTP, normal mf LTPh Agonists facilitate STD into persistent (>24 h) LTDg; Antagonists impair LTD in CA1 & DGiJ;

II mGlu2,3 Agonists raise LTP thresholdk; Antagonists have no effect1*1 Knockouts: normal mf LTPm Agonists facilitate STD into LTDn; Antagonists block persistent LTDl

III mGlu4,7,8 Agonists raise LTP thresholdk; Antagonists have no effecto,p Agonists facilitate STD into LTDq; Antagonists block persistent LTDp

Abbreviations: dentate gyrus (DG); long-term potentiation (LTP); long-term depression (LTD); mossy fibre (mf); short-term depression (STD); short-term potentiation (STP). a Naie and Manahan-Vaughan, 2005. b Neyman and Manahan-Vaughan, 2008. c Aiba et al.,1994. d Conquet et al., 1994. e Manahan-Vaughan,1997. f Kulla and Manahan-Vaughan, 2008. g Ayala et al., 2009. h Luetal., 1997.

1 Popkirov and Manahan-Vaughan, 2011. j Naie and Manahan-Vaughan, 2004. k Kulla et al.,1999.

l Altinbilek and Manahan-Vaughan, 2009. m Lyonetal., 2011. n Poschel et al., 2005. o Klausnitzer et al., 2004. p Altinbilek and Manahan-Vaughan, 2007. q Naie and Manahan-Vaughan, 2006.

suggests that the contribution of this receptor to synaptic plasticity may not be simply constrained to the downstream signalling cascades that are regulated by mGlul. This possibility was confirmed in both in vitro (Neyman and Manahan-Vaughan, 2008) and in vivo studies (Naie and Manahan-Vaughan, 2005), where it was shown that antagonism of mGlul results in an inhibition of the induction phase of LTP. Evidence exists that mGlul may regulate NMDAR currents (Skeberdis et al., 2001) and that mGlul is necessary for NMDAR cycling (Lan et al., 2001). Thus, the effects of mGlul antagonism on the induction phases of LTP may relate to a disruption of these elements, as persistent hippocampal LTP is NMDAR-dependent (Manahan-Vaughan, 1997). Furthermore, it has been shown that mGlul must be activated during the tetanus in order for LTP to be induced (Raymond et al., 2000).

Studies using transgenic animals that lack mGlul support these findings: in one study impaired CA1 LTP was reported (Aiba et al., 1994), in another, impaired mossy fiber LTP was described (Conquet et al., 1994). These studies were conducted in vitro. As this review focuses on long-lasting (>4 h) forms of plasticity, it will not address pharmacological studies in vitro, where plasticity was typically followed for periods of ca. 60 min (see Anwyl, 1999, 2009, for reviews).

2.1.2. mGlu 5 in persistent LTP

Whereas, mGlu1 is involved in LTP induction and not directly in LTP maintenance, mGlu5 plays a significant role in both the induction and maintenance phases of persistent LTP (Balschun and Wetzel, 2002; Naie and Manahan-Vaughan, 2004; Manahan-Vaughan and Braunewell, 2005; Neymann and Manahan-Vaughan, 2008). Activation of mGlu5 leads to suppression of the calcium-activated potassium current (IAHP) and an enhancement of NMDAR currents (Jia et al., 1998; Mannaioni et al., 2001; Attucci et al., 2001 ). In line with this, the NMDAR component of LTP is abolished in mGlu5 knock-out mice (Wojtowicz and Roder, 1998).

urthermore, induction of both persistent (>24 h) LTP (Manahan-Vaughan et al, 2003), and the acquisition of spatial memories (Riedel et al., 2000) leads to increased hippocampal expression of mGlu5. In addition, dendritic protein synthesis is triggered by mGlu5 (Huber et al., 2000, 2001). Taken together this suggests that mGlu5 also contributes to synaptic restructuring that upholds persistent information storage.

The influence of mGlu5 on hippocampal function is manifold. One study that addressed the consequences of prolonged mGlu5 antagonism on hippocampus-dependent phenomena reported that a loss of spatial memory was accompanied by impairment of LTP in the dentate gyrus, and enhancement of the early (induction) phases of LTP in the CA1 region (Bikbaev et al., 2008). These effects were associated with a disruption of theta-gamma neuronal oscillations in the dentate gyrus. These findings suggest, on the one hand, that mGlu5 may be responsible for maintaining LTP in a physiological range: either too little or too much (saturation) could lead to memory impairments due to disrupted synaptic information storage. On the other hand, the findings also suggest that mGlu5 contributes to information transfer enabled by neuronal oscillations. Failure to express LTP is linked with failure to increase the power of theta-gamma activity in the hippocampus (Bikbaev and Manahan-Vaughan, 2007, 2008). Both theta and gamma power were significantly decreased in animals treated with an mGlu5 antagonist (Bikbaev et al., 2008). Gamma activity is believed to reflect synchronisation processes within neuronal assemblies (Bragin et al., 1995; Kocsis et al., 1999; Chrobak and Buzsaki, 1998). The loss of theta-gamma power mediated by mGlu5 antagonism suggests that this receptor supports theta-gamma oscillation-mediated temporal organisation of information processing. This may in turn explain why disruptions or changes in expression of mGlu5 have such dramatic effects on cognition and memory in the brain (Fatemi and Folsom, 2011; Giuffrida et al., 2005).

2.1.3. Role of group II mGlu receptors in persistent LTP

With regard to their role in synaptic plasticity, group II mGlu receptors are distinct from group I receptors in that they do not regulate multiple forms of plasticity. Although antagonists of these receptors prevent persistent LTD (see Section 2.2.2 below), they do not influence LTP (Manahan-Vaughan, 1997; Kulla et al., 1999; Altinbilek and Manahan-Vaughan, 2009). Nonetheless, agonists of mGlu II receptors impair LTP, presumably by altering the induction thresholds for this phenomenon. Agonist concentrations that do not affect basal synaptic transmission prevent persistent LTP (Kulla et al., 1999). As mentioned above (Section 1), group II mGlu receptors are predominantly presynaptically localised outside of the synapse and, through inhibition of adenylyl cyclase, can alter presynaptic glutamate release (Lujan et al., 1997; Dietrich et al., 2002; Losonczy et al., 2003). This is presumed to be the mechanism whereby activation of these receptors raises the threshold for LTP induction. In a recent in vitro study, it was reported that in a double knockout, where mice lacked both mGlu2 and mGlu3, mossy fiber LTP was intact (Lyon et al., 2011a). This was curious finding, given multiple documentations that application of agonists of group II mGlu receptors completely abolishes synaptic transmission at mossy fiber synapses (Kamiya et al., 1993; Yeckel et al., 1999; Goussakov et al., 2000).

Few studies have addressed the independent role of mGlu2 and mGlu3 on persistent (>4 h) or short-term (<4 h) synaptic plasticity. Antagonist studies have shown that blocking mGlu3 has no effect on persistent LTP, whereas agonist application reduced the magnitude and longevity of LTP such that short-term potentiation (<3 h) results (Poschel et al., 2005).

2.1.4. Role of group III mGlu receptors in persistent LTP

Activation of group III mGlu receptors inhibit LTP in vivo, with

a variation in sensitivity to the drug occurring between hippocampal subregions (Manahan-Vaughan and Reymann, 1995; Klausnitzer et al., 2004). This most likely relates to the expression of group III receptors in the hippocampus as described in Section 1. In effect, treatment with a group III agonist results in reduced induction of synaptic potentiation and a curtailed duration of plasticity. This effect is very similar to that seen following application of group II mGlu agonists (Kulla et al., 1999), which is not that surprising given that both receptor families are presynaptically localised and, when activated, reduce glutamate release. In contrast, application of antagonists of group II receptors have no effect on LTP (Klausnitzer et al., 2004; Altinbilek and Manahan-Vaughan, 2007).

As with group III mGlu receptors, few studies have addressed subtype specific effects. Interestingly however, mice that lack mGlu7 show higher theta oscillatory activity in the hippocampus, whereas gamma activity remained unchanged (Holscher et al., 2005). Given the fact that parallel alterations in theta-gamma activity are required for successful LTP (Bikbaev et al., 2008) this finding may explain why working memory is impaired in these mice (Holscher et al., 2005).

2.2. Persistent LTD

Persistent (>24 h) long-term depression (LTD) in the hippocampus has distinct molecular specifications depending on the subregion concerned. In the CA1 region, persistent LTD is NMDAR-dependent and requires protein synthesis (Manahan-Vaughan, 1997; Manahan-Vaughan et al., 2000), whereas in the dentate gyrus it is NMDAR-independent and voltage-gated calcium channel independent and does not require protein synthesis (Poschel and Manahan-Vaughan, 2007). Currently, not that much is known about persistent LTP in the CA3 region, although a recent study confirms in vitro reports that mossy fiber LTP does not require NMDA receptors (Hagena and Manahan-Vaughan, 2011) but

requires protein synthesis (Hagena and Manahan-Vaughan, unpublished data). Nothwithstanding these differences, it has become apparent that all forms of persistent LTD that have been studied to date require the contribution of mGlu receptors (Manahan-Vaughan, 1997; Altinbilek and Manahan-Vaughan, 200 , 2009).

In neonatal animals, mGlu-dependent LTD has been described (Bolshakov and Siegelbaum, 1994; Oliet et al., 1997). Furthermore, in cultured hippocampal neurons, activation of group I mGlu receptors results in chemically-induced LTD (Snyder et al., 2001; Xiao et al., 2001) which is insensitive to PKC inhibitors (Gallagher et al., 2004; Wu et al., 2004). Appropriate synaptic stimulation of the Schaffer collaterals can also induce an mGlu5-dependent and NMDAR-independent LTD, which occludes chemical LTD induced by the group I agonist, dihydroxyphenylglycine (DHPG), (Huber et al., 2001). These phenomena are believed to be post-synaptically mediated, but other evidence suggests the existence of a presynaptically-mediated form of mGlu-dependent LTD (Malenka and Bear, 2004). In adult animals, chemically-induced persistent LTD (>24 h) has also been described that is elicited by activation of group I (Naie et al., 2007) group II (Pöschel et al., 2005) and group III mGlu receptors (Manahan-Vaughan and Reymann, 1995). However, a dissociation from NMDAR-mediated effects was not fully explored. In the dentate gyrus, LTD elicited by group I agonists is NMDA receptor-and voltage-gated calcium channel -dependent, rendering it a distinct phenomenon from persistent LTD induced by patterned electrical stimulation (Pöschel and Manahan-Vaughan, 2005).

2.2.1. Role of group I mGlu receptors in persistent hippocampal LTD

Several studies have addressed the role of group I mGlu receptors in persistent (>24 h) LTD, although fewer have examined subtype-specific effects. Use of general antagonists of group I mGlus prevents persistent LTD (Manahan-Vaughan, 1997; Kulla and Manahan-Vaughan, 2008). In contrast to reports with regard to LTP, however, antagonism of mGlu1 leads to an impairment of both the induction and maintenance phases of persistent LTD (Neymann and Manahan-Vaughan, 2008). In contrast, antagonism of mGlu5 reduces the induction phase but leaves the maintenance and longevity of LTD intact (Neymann, 2008). These observations provoke the question as to how antagonism of group I mGlu receptors can affect such diametrically opposed forms of synaptic plasticity. The regulation by group I mGlu receptors, or more specifically, by mGlu5 of LTD is protein-synthesis-dependent (Neymann and Manahan-Vaughan, 2008). In addition, the contribution of group I mGluRs to LTP and LTD is determined by the frequency of afferent activity as well as the intracellular calcium signal generated by activation of the receptor (Harney et al., 2006; Naie et al., 2007). This is also the case for synaptic plasticity per se (Frey et al., 1988; Lisman, 1989; Dudek and Bear, 1992; Artola and Singer, 1993; Cummings et al., 1996; Manahan-Vaughan, 2000). Thus, it is not unreasonable to assume that specific afferent activation patterns recruit group I mGlu receptors to differing extents that in turn trigger protein synthesis that supports very specific forms of synaptic plasticity. In line with this, a recent study suggest that competition between mGlu5 and NMDARs may drive the bidirectionality of synaptic responses to afferent stimulation (Hsu et al., 2011).

2.2.2. Role of group II mGlu receptors in persistent hippocampal LTD

Group II mGlu activation is critically required for persistent LTD

induction and maintenance (Manahan-Vaughan, 1997; Klausnitzer and Manahan-Vaughan, 2008; Altinbilek and Manahan-Vaughan, 2009). Effects occur using ligands that do not exert independent effects on basal synaptic transmission. However, it is possible that

the antagonists prevent glutamate-mediated feedback onto presynaptic group II mGlu receptors that under normal circumstances would lead to reduced glutamate release onto the synapses that activate the machinery for induction of synaptic plasticity. Little is known about the contribution of group II mGlu sybtypes, although it has been reported that mGlu3 activation is required for long-lasting LTD (Pöschel et al., 2005).

In shorter-lasting forms of synaptic depression, conflicting results have been reported. For example, one transgenic study on mice lacking mGlu2 reports that this receptor is not required for LTD (<1 h), whereas another transgenic study reported the opposite (Yokoi et al., 1996). Interestingly, priming of group II mGlu receptors facilitates LTD in vivo (Manahan-Vaughan, 1998) but inhibits it in vitro (Mellentin and Abraham, 2001). This may relate to the hippocampal subfield studied (dentate gyrus in vivo versus CA1 in vitro) or to the finding that the agonist used in the in vitro study also activates NMDARs (Breakwell et al., 1997). The same agonist was effective in inducing LTD in the dentate gyrus (Manahan-Vaughan, 1998), but whereas LTD in this structure is NMDAR-independent, in the CA1 region it is not (Manahan-Vaughan, 1997; Pöschel and Manahan-Vaughan, 2005, 2007). In another study in hippocampal slices, it was shown that activation of group II mGlus with DCG-IV coupled to weak afferent stimulation leads to LTD in the CA1 region (Santschi et al., 2006), suggesting that experimental conditions may have a significant influence on the outcome of in vitro studies.

2.2.3. Role of group III mGlu receptors in persistent hippocampal LTD

Antagonism of group III mGlu receptors impairs the expression of persistent (>24 h) LTD, but not LTP, in both the CA1 region and dentate gyrus (Klausnitzer et al., 2004; Altinbilek and Manahan-Vaughan, 2007). Here, antagonist application prevents LTD from persisting for more than 1—2 h, although under control conditions it would last for days. In transgenic animals that lack mGlu7, short-term plasticity is impaired (Bushell et al., 2002). This receptor appears to be pivotal for bidirectional plasticity at the mossy fiber synapses, where the direction of change of synaptic weight is determined by the relative activation and expression state of the receptor (Pelkey et al., 2005). In the CA1 region, mGlu7 is strongly expressed on Schaffer collaterals, whereas mGlu4 is presynaptically localized on axons, and postsynaptically on pyramidal cell soma and dendrites (Bradley et al., 1996). Thus effects on LTD are likely to be mediated by these subtypes.

Chemically-induced LTD (>4 h) has been described following application of a group III mGlu agonist (Naie and Manahan-Vaughan, 2006). Although group II mGlu receptors function as autoreceptors for glutamate, effects are associated with changes in neuronal viability: in the CA1 region cells were protected by intracerebral application of the agonist L(+)-2-amino-4-phosphonobutanoic acid (AP4), whereas in the dentate gyrus cell viability was reduced (Naie and Manahan-Vaughan, 2006).

2.3. Depotentiation

Depotentiation comprises a reversal of LTP achieved by using low frequency afferent stimulation within minutes of applying an LTP induction protocol (Barrionuevo et al., 1980; Staubli and Lynch, 1990; Fujii et al., 1991). Depotentiation has been demonstrated both in vivo in CA1 (Barrionuevo et al., 1980; Staubli and Lynch, 1990; Staubli and Chun, 1996) and in the dentate gyrus (Kulla et al., 1999). Depotentiation is distinct from long term depression, requiring a different array of AMPA receptor dephosphorylation (Lee et al., 2000) and requiring different mGlu receptors (Kulla et al., 1999; Klausnitzer et al., 2004). Group II mGlu priming increases the LFS-

induced depotentiation in the dentate gyrus in vivo whereas antagonists prevent this effect (Kulla et al., 1999). Group II mGlu activation also blocks the low frequency stimulation-induced depotentiation in the CA1 region in vivo (Holscher et al., 1997). Activation of group III mGlu receptors is critically required for LTD, but not LTP or depotentiation in the dentate gyrus, and this finding provides evidence for the involvement of separate mechanisms underlying LTD and depotentiation (Klausnitzer et al., 2004). Group I mGlu receptors are also critically involved in dentate gyrus in vivo in depotentiation (Kulla and Manahan-Vaughan, 2008). Subtype-specific roles of group I mGlu receptors in depotentiation in vivo have not been addressed, but in vitro data suggest that a subtype variance exists with regard to group I mGlu-mediated depot-entiation (Hu et al., 2005; Zho et al., 2002).

2.4. Learning-facilitated forms of synaptic plasticity

Learning-facilitated synaptic plasticity refers to the ability of hippocampal synapses to respond with persistent synaptic plasticity to the coupling of weak afferent stimulation, which is subthreshold for the induction of plasticity, with a spatial learning experience (Manahan-Vaughan and Braunewell, 1999; Kemp and Manahan-Vaughan, 2004, 2007). This phenomenon has been observed in the three main hippocampal subregions (Kemp and Manahan-Vaughan, 2004, 2008; Hagena and Manahan-Vaughan, 2011) where for example, exposure to a new spatial environment potently facilitates the longevity of LTP. Facilitation of LTD in the CA1 region and in commissural associational synapses of the CA3 region occurs in response to exploration of minor features of a spatial context (Manahan-Vaughan and Braunewell, 1999; Kemp and Manahan-Vaughan, 2004; Hagena and Manahan-Vaughan, 2011). Spatial constellations of large navigational cues facilitate LTD in the dentate gyrus and in mossy fibre-synapses of the CA3 region (Kemp and Manahan-Vaughan, 2008; Hagena and Manahan-Vaughan, 2011). In addition, depotentiation in the CA1 region and the dentate gyrus has been shown when rats explore a novel environment (Xu et al., 1998; Abraham et al., 2002).

Recently, it was reported that learning-facilitated plasticity in the CA1 region requires mGlu5. Here, application of the negative allosteric modulator (NAM), MPEP (5-methyl-2-(2-phenylethynyl) pyridine) (Gasparini et al., 1999) prevented both learning of the spatial context and the facilitation of LTD that was seen when the animals explored novel constellations of objects in a spatial environment. This finding underlies the close link, on the one hand between synaptic plasticity and learning, and on the other hand, the pivotal role of mGlu receptors in both persistent synaptic plasticity and long-term learning.

2.5. Role of mGlu receptors in metaplasticity

Metaplasticity describes a higher order form of synaptic plasticity, in which synaptic experience leads to subtle changes in the propensity of synapses to express synaptic plasticity. Here, changes are not immediately detectable, rather the prior experience of the synapses alters subsequent responses to plasticity-inducing afferent stimulation (Deisseroth et al., 1995; Abraham and Bear, 1996) and can even alter the direction of change of synaptic weights (Kemp and Manahan-Vaughan, 2005; Zhang et al., 2005). The prior activation of mGlu receptors is one of the factors that drives metaplasticity (Manahan-Vaughan et al., 1996). However, the activation of NMDA receptors (Mockett et al., 2002), afferent priming of a synapse (Wang and Wagner, 1999) and the behavioural state of an animal (Manahan-Vaughan and Braunewell, 1999) all can strongly influence the subsequent expression of synaptic plasticity. One purpose for metaplasticity may be to prevent

saturation of synaptic plasticity, and thereby keep LTP and LTD in a dynamic functional range.

The contribution of mGlu receptors to metaplasticity is manifold. For example, group I mGlu receptor activation facilitates both induction and persistence of LTP. The former process is mediated on the one hand by inhibition of the Ca2+-activated, K+-channel-mediated, slow afterhyperpolarization (Cohen et al., 1999), and on the other hand by activation of adenylyl cyclase by mGlu receptor-mediated activation of PKC and subsequent Ca2+ release from intracellular sources (Ireland and Abraham, 2002). This leads to PKA-mediated phosphorylation of the Ser845 site of the GluA1 subunit of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, a step necessary for membrane insertion of GluA1 containing AMPA receptors (Oh et al., 2006; Gao et al., 2006).

Group I mGlu receptor activation also facilitates the persistence of LTP independent of its effect on LTP induction. High-frequency stimulation of synapses containing group I mGlu receptors sets up a 'molecular switch' which abolishes the need for these receptors to be activated by subsequent stimulation in order to generate persistent LTP (Bortolotto et al., 1994). Effects only occur in primed synapses and last for an hour (Bortolotto et al., 1995). Setting of the switch is mediated by mGlu5-activated CaMKII and PKC (Bortolotto et al., 1998, 2000, 2005).

Furthermore, prior pharmacological priming of group I mGlu receptors transforms a decaying form of LTP into a stable one (Cohen et al., 1998; Cohen and Abraham, 1996; Raymond et al., 2000) and short-term potentiation in to LTP in the dorsal hippocampus (Manahan-Vaughan and Reymann, 1996). Effects are also evident in the ventral hippocampus (Maggio and Segal, 2007). This action is mediated by PLC-dependent Ca2+ release from intracel-lular stores as well as through membrane calcium channels (Abraham, 2008). All of these pathways lead to enhanced local protein synthesis in synapses (Raymond et al., 2000) that support the persistence of subsequently generated LTP. The effect of priming stimulation of mGlu receptors is opposite in action in the medial perforant path of dentate gyrus, where prior pharmacological activation of group I mGlu receptors leads to subsequent inhibition of LTP mediated by PKC and p38 MAPK mechanism (Gisabella et al., 2003).

Metaplastic effects of mGlu receptors are neither restricted to group I receptors nor to LTP, however. Priming of group II but not group III mGlu receptors facilitates the expression of LTD in the dentate gyrus (Manahan-Vaughan, 1998; Klausnitzer et al., 2004). Priming of group II mGlu receptors also inhibits successful LTP in the dentate gyrus and CA1 regions (Manahan-Vaughan and Reymann, 1995).

3. Spatial learning in rodents

Spatial learning in rodents is tightly correlated to different forms of hippocampal synaptic plasticity, and a number of reviews have already addressed transgenic studies where reports of alterations in the ability to perform in memory tasks occurred in animals that experienced changes in their ability to express synaptic plasticity (Braunewell and Manahan-Vaughan, 2001; Morris et al., 2003; Lynch, 2004). All of those studies were "observational" i.e. no attempt was made to correlate the changes seen in memory with the changes seen in synaptic plasticity. They served the useful purpose however, of drawing attention to the fact that a relationship exists between these phenomena. More recently, studies have attempted to examine the relationship between synaptic plasticity and learning more closely. For example, long-term potentiation (LTP) appears to be linked to spatial memory processing, although different learning conditions elicit different effects: learning about novel empty space facilitates LTP at selected synapses within the

trisynaptic circuit (Kemp and Manahan-Vaughan, 2007, 2008; Hagena and Manahan-Vaughan, 2011), but novel spatial learning in a holeboard impairs early-LTP (Makhracheva-Stepochkina et al., 2008). In contrast, fear-conditioning promotes hippocampal synaptic potentiation (Whitlock et al., 2006). Furthermore, deficits in spatial alternation are linked to deficits in long-term depression (LTD) (Nakao et al., 2002), and the consolidation of spatial memory is reported to require LTD (Ge et al., 2010). Context-specific spatial memory is also associated with LTD (Etkin et al., 2006; Kemp and Manahan-Vaughan, 2007; Popkirov and Manahan-Vaughan, 2011; Goh and Manahan-Vaughan, in press).

To study spatial learning in rodents, a variety of different behavioural learning paradigms are implemented. Here, one typically aims to differentiate between short-term/working memory (Olton and Papas, 1979), meaning spatial memory that is maintained simply for as long as the task is in process (Funahashi and Kubota, 1994; Baddeley, 1992) and long-term/reference memory. The former type of memory can be considered as enabling the holding of information "online" and serves the purpose of completing the (memory) task at hand. Long-term or reference memory, refers to spatial memory that enables recollection of the goals of task that is sustained also in the interim where no task performance is required. This type of memory is usually sustained for hours, days or even weeks in rodents (Abraham et al., 2002; Staubli and Lynch, 1987). Place field formation is also a component of spatial learning, specifically in the context of the development of a metric map of the environment (Agnihotri, 2004, Mizumori, 2006; Silva et al., 1998; O'Keefe and Burgess, 1996). However, no study has at yet addressed the issue of the contribution of mGlu receptors to this phenomenon.

3.1. Animal models of hippocampus-dependent learning

Studies of reference memory are traditionally conducted in the Morris water maze (Morris, 1984; D'hooge and Deyn, 2001; Vorhees and Williams, 2006) (Fig. 1A). Here, the development of this form of long-term spatial memory over a period of hours, days or weeks can be observed. In effect the animal learns the location of a platform hidden below the surface of the opaque water of the maze. The 8-arm radial maze allows the delineation of working memory from reference memory (Olton and Papas, 1979; Prior et al., 1997; Naie and Manahan-Vaughan, 2004) (Fig. 1B). Here, the animal learns the spatial locations of food rewards that are located at the end of the maze arms.

Fear conditioning is considered a form of context-specific associative learning that is hippocampus-dependent (Kim and Fanselow, 1992; Philips and LeDoux, 1992) and requires NMDA receptors (Kim et al., 1991). Fear conditioning shares molecular mechanisms with hippocampal LTP and elicits synaptic potentia-tion in the CA1 region (Whitlock et al., 2006). In this paradigm, typically a conditioned stimulus which is perceived as neutral, such as a recording chamber or a tone, is subsequently coupled with an aversive, unconditioned stimulus, such as an electric shock. A conditioned freezing response is usually observed as a consequence of exposure to the "neutral" stimulus.

Although there is some debate as to whether object recognition memory (Fig. 1C) requires the participation of the hippocampus, evidence exists that the hippocampus contributes to this form of learning by integrating spatial and non-spatial inputs that converge on the hippocampus (Manns and Eichenbaum, 2006, 2009). In addition, it is likely that spatial and "temporal order" elements of object recognition are hippocampus-dependent (Fortin et al., 2002; Manns and Eichenbaum, 2006, 2009; Manns et al., 2007; Farovik et al., 2010). In support of this likelihood, a recent study highlighted the very tight relationship between object recognition and

E B CO

v_J V_J

Fig. 1. A. The Morris water maze. The Morris water maze is used to study long-term spatial memory. Here, the rodent swims in a large pool of water that is made opaque by substances such as titanium dioxide. The pool is designated into 4 quadrants by the experimenter. Over a period of multiple training sessions (usually several per day for up to 3 weeks) a platform is continuously placed in one of the quadrants. The surface of the platform is located below the surface of the water and cannot be seen by the rodent. The rodent learns the location of the platform by using visual cues that are located in the room. After learning performance is significantly above chance, a transfer test is conducted where the platform is removed. Here, the time set looking for the platform in the target quadrant is compared with time spent in the other quadrants. B. The Radial maze. The radial maze is used to distinguish working from reference memory. In the spatial version of the task, a food pellet (or fluid reward) is placed at the end of each of four arms of the radial maze. The four arms are selected randomly at the start of the study but are subsequently kept constant for the test animal concerned. A return during a given trial to an arm, in which a reward had already been retrieved, is deemed a working memory error- as the animal should recall that it has retrieved food and that none remains. Entry into an arm where food has never been included is deemed a reference memory error- as here the animal should recall that this arm is never "baited" from trial to trial. Within this context, re-entry into never-baited arms can also be considered a combined working and reference memory error (Prior et al., 1997). C. Object recognition. The object recognition task capitalises on the innate willingness of rodents to explore newer objects in comparison to previously encountered ones (Clark and Martin, 2005). Quite simply the rodent is presented with a selection of objects (often 2, sometimes 4) and allowed to explore them for a period of minutes. Following a delay of minutes to hours or days, the rodent is re-exposed to the objects, except this time half are objects that were seen in the first exposure and half are new. Under normal conditions the animals are expected to explore the novel objects more than the familiar ones.

learning-facilitated synaptic plasticity in the mouse (Goh and Manahan-Vaughan, in press). Here, engaging in object recognition led to the occurrence of intrinsic long-term depression (LTD) in the hippocampus of behaving mice.

4. Role of group I mGlu receptors in spatial memory

Metabotropic glutamate receptors are very dominant in multiple forms of hippocampal synaptic plasticity both in vivo and in vitro, ranging from slow-onset potentiation and LTP, through chemical depression and protein synthesis-dependent and -independent forms of LTD (Manahan-Vaughan and Reymann, 1995; Manahan-Vaughan, 1997; Huber et al., 2001; Naie and Manahan-Vaughan, 2004, 2005; Naie and Manahan-Vaughan, 2006; Manahan-Vaughan and Braunewell, 2005; Moult et al., 2006; Poschel and Manahan-Vaughan, 2005; Poschel et al., 2005). This suggests a dominant role for these receptors in synaptic information storage and hippocampus-dependent forms of memory (Table 3).

4.1. mGlu1

The first studies as to the role of mGlu1 in spatial memory were conducted in transgenic animals in the early 1990s. Here, using the water maze it was reported that mice lacking mGlu1 exhibit deficits in reference memory. In one study, basal synaptic transmission and

LTD that was examined for a total of 20 min was normal. However the magnitude of LTP was curtailed and context-dependent fear conditioning was impaired (Aiba et al., 1994). Spatial learning was not examined in this study, but a second study that was published in the same year, reported that reference memory in the water maze is impaired in these animals (Conquet et al., 1994). Here, mossy fiber but not associational-commissural LTP in the CA3 region, as well as cerebellar LTD that were each followed for 60 min were significantly reduced. As an aside: recently it was shown that deficits in cerebellar plasticity are associated with marked impairments in the spatial navigational function of the hippocampus (Rochefort et al., 2011), thus a causal relationship between the hippocampal memory and cerebellar plasticity effects seen in the mGlu1 mice cannot be excluded.

Several pharmacological studies have addressed the role of mGlu1 in spatial and contextual memory processing. For example, it was reported that inhibiting mGlu1 facilitates, and positive allosteric modulation of mGlu1 impairs, consolidation of fear memory (Maciejak et al., 2003). Ligands of mGlu5 were ineffective suggesting a specific involvement of mGlu1 in this memory process. The authors speculate that increased glutamatergic transmission during the memory consolidation phase is contra-productive and that mGlu1 may serve to regulate these levels. A role for mGlu1 in the acquisition of context-specific memory and in the extinction of inhibitory avoidance learning has also been described (Gravius et al., 2006; Simonyi et al., 2007). Trace eye-

Table 3

Table provides an overview of the role of mGlu receptors in different types of hippocampus-dependent memory.

Group Sub—type Water maze

Radial maze

Spatial context learning

Fear conditioning

I mGlul Deficits in KO micea

mGlu5 Deficits in KO miceg;

PAM improves performance11

mGlu2,3 Performance improved by agonistsn;

No effects in KO mice in an aversely motivated tasko mGlu4,7,8 No deficits in mGlu4 KO mice during the task, but deficits in long-term memory were evidents

Antagonist: Reference memory impaired, working memory intactb

NAM: Reference & working memory impairedi

Reference memory impaired by antagonistp; Deficits in KO mice in an appetitively motivated taskq Antagonist prevents reference but not working memoryt; Working memory deficits in mGlu7 KO miceu v

Involved in context-specific memory and inhibitory avoidance learningc,d; KO mice have impaired trace eye-blink conditioninge

NAM impairsj and PAM improvesk spatial alternation;

NAM impairs inhibitory avoidance learning, object recognition and object-place learningd,l,m Passive avoidance impaired by agonistsq; Co-application of a group II antagonist with an mGlu5 antagonist prevents object recognition memoryl.

Antagonist reduces habituation to complex

odor-driven behaviourw;

Spatial alternation deficits in mGlu7 KO miceu

Impaired in KO micea; agonists facilitate, antagonists impairf.

mGlu5 antagonists impairc

Impairment by agonistsr

Abbreviations: knock-out (KO); negative allosteric modulator (NAM); positive allosteric modulator (PAM). a Aiba et al., 1994. b Naie and Manahan-Vaughan 2005. c Gravius et al., 2006. d Simonyi et al., 2007. e Gil-Sanz et al., 2008. f Maciejak et al., 2003. g Luetal., 1997. h Balschun et al., 2006.

i Naie and Manahan-Vaughan 2004. j Balschun et al., 2002. k Ayala et al., 2009. l Barker et al., 2006.

m Popkirov and Manahan-Vaughan, 2011. n Higgins et al., 2004. o Lyon etal., 2011.

p Altinbilek and Manahan-Vaughan, 2009. q Sato et al., 2004. r Daumas et al., 2009. s Gerlai et al., 1998.

t Altinbilek and Manahan-Vaughan, 2007. u Holscher et al., 2004.

v Holscher et al., 2005. w Yadon and Wilson, 2005.

blink conditioning is also impaired in mice lacking mGlu1 (Gil-Sanz et al., 2008). In addition, inhibition of reference memory in the water maze has been described (Schroder et al., 2008). Naie and Manahan-Vaughan (2005) reported that antagonism of mGlu1 prevents reference, but not working, memory in the 8-arm radial maze and that these effects are associated with deficits in the NMDA receptor-dependent induction phase of LTP. Others have shown that mGlu1 regulates currents through NMDA receptors (Mannaioni et al., 2001; Skeberdis et al., 2001), a suppression of which could lead to a reduction in the magnitude of LTP induced.

4.2. mGlu5

Early studies using mGlu5 knock-outs revealed a slightly different profile as reported for mGlu1 transgenics (Lu et al., 1997). Here, mossy fiber LTP was intact but CA1 and dentate gyrus LTP were impaired. Memory impairments in both the water maze and in fear-conditioning were also noted. With regard to other hippocampus-dependent learning paradigms, a reduction in retention of inhibitory avoidance learning and in spatial alternation was reported in animals treated with the negative allosteric modulator (NAM), MPEP (Balschun et al., 2002; Simonyi et al., 2007). By contrast, application of a positive allosteric modulator (PAM) improved spatial alternation (Balschun et al., 2006).

mGlu5 PAMS enhance both LTP and LTD in the hippocampus, as long as the plasticity response is not already very robust (Ayala

et al., 2009). The same PAMs also enhance spatial learning in the water maze (Ayala et al., 2009). In line with this, Naie and Manahan-Vaughan (2004) described that antagonism of mGlu5 results in impairments of both working and reference memory in an 8-arm radial maze, and mGlu5 NAM treatment prevents LTD that is facilitated by spatial context learning (Popkirov and Manahan-Vaughan, 2011). A marked impairment of early-LTP, late-LTP and LTP maintenance following antagonism of mGlu5 was also reported in the former study (Naie and Manahan-Vaughan, 2004). A loss of the NMDA receptor component of LTP has been reported in mice lacking mGlu5 (Jia et al., 1999), whereas facilitation of NMDA currents (Attucci et al., 2001) along with LTP of the NMDA receptor mediated by mGlu5 has also been described (Jia et al., 2001). Furthermore, Raymond et al. (2000) reported that group I mGlu receptors trigger protein synthesis required for LTP and Huber et al. (2000) showed that activation of mGlu5 stimulates dendritic protein synthesis. These effects may serve to explain the effects on reference memory seen in this study.

Co-application of an mGlu5 antagonist with an antagonist of group II mGlu receptors prevents object recognition memory using mechanisms that also involve the perirhinal cortex (Barker et al., 2006). Possible joint effects of these receptors were described using first generation mGlu antagonists, such as MCPG (a-methyl-4-carboxyphenylglycine), where impairments of spatial alternation performance (Riedel et al. 199b) and spatial learning in the water maze were reported (Richter-Levin et al., 1994; Bordi et al., 1996).

Application of an mGlu5 PAM, 2-methyl-6- (phenylethynyl) pyridine (MPEP), prevents object-place learning (Popkirov and Manahan-Vaughan, 2011).

Interestingly, good and bad spatial learners exhibit different expression levels of mGlu5 (Manahan-Vaughan and Braunewell, 2005). Two rat strains were studied. Wistar rats were found to express persistent LTP (>24 h) and exhibit robust reference memory in an 8-arm radial maze. By contrast, Hooded Lister rats expressed only short-term potentiation (STP) in response to the same tetanisation protocol and demonstrated reliable reference memory. Wistar rats expressed significantly more hippocampal mGlu5 than Hooded Lister rats and were far more sensitive to treatment with the NAM, MPEP. In addition, group I mGlu receptors may become significant for memory processing when the task is challenging. Antagonism of group I mGlus, using(S)4-carbox-yphenylglycine (4-CPG), had no effect on spatial alternation unless the task was made more difficult (Balschun et al., 1999). This antagonist, also prevents reference memory in the 8-arm radial maze (Balschun et al., 1999).

It is worth mentioning that antagonism of mGlu5 elicits alterations in EEG activity such that delta (slow wave) activity becomes prominent (Binns and Salt, 2001). Changes in theta-gamma coupling also occur (Bikbaev et al., 2008), which are associated with a loss of dentate gyrus LTP, an increase in the early component of LTP in the CA1 region and impairments of working a reference memory. This suggests that the regulation by mGlu5 of hippocampus spatial memory may occur by means of the ringhold this receptor exerts on processes related to information transfer and information storage in the hippocampus.

5. Role of group II mGlu receptors in spatial memory

Separate studies on the roles of mGlu2 and mGlu3 on hippocampus-dependent memory have not been reported, due to the fact that knock-outs have not been explored and there are few highly selective ligands for these receptors. One electrophysiolog-ical study reported a separate role for mGlu3 in synaptic plasticity. Here, for example, LTP was impaired and LTD was enhanced by an mGlu3 agonist (Poschel et al., 2005), but one has to consider that the agent used (N-acetylaspartylglutamate (NAAG)) may have actions on NMDA receptors (Fricker et al., 2009). In the former study, NAAG effects were prevented by the selective group II mGlu antagonist (2S)-alpha-ethylglutamic acid (EGLU), suggesting that effects were mediated predominantly by group II mGlu receptors.

All studies on hippocampus-dependent behaviour to date have been done with combined ligands or allosteric modulators of group II mGlu receptors. Altinbilek and Manahan-Vaughan (2009) reported that EGLU prevented reference memory in an 8-arm radial maze and impaired LTD in the CA1 region. EGLU does not affect LTP in the CA1 region (Manahan-Vaughan, 1997). Similarly no effect was seen on LTP and LTD in the dentate gyrus (Altinbilek and Manahan-Vaughan, 2009). This raises the interesting question as to whether this type of spatial learning is mediated by LTD in the CA1 region of the hippocampus.

Interestingly, agonist activation of group II mGlu receptors impairs contextual fear memory (Daumas et al., 2009). The ligand used: (2S, 1'R, 2'R, 3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), not only suppresses mossy fiber transmission in the CA3 region in vivo (Klausnitzer and Manahan-Vaughan, 2008; Hagena and Manahan-Vaughan, 2010), but also facilitates LTD at perforant path- dentate gyrus synapses (Manahan-Vaughan, 1998). Thus, it is all the more striking that only infusion of DCG-IV into the CA3 region led to an inhibition of contextual fear memory (Daumas et al., 2009), suggesting that this hippocampal subregion mediates this phenomenon.

Reports on the effects of agonists of group II mGlu receptors on hippocampus-dependent learning are varied: some report impaired learning in a spatial working memory T-maze task (Aultman and Moghaddam, 2001; Gregory et al., 2003), others report an improvement in working memory performance in a T-maze (Gregory et al., 2003) and in reference memory in the water maze (Higgins et al., 2004). Performance in a passive avoidance task is impaired by group II mGlu receptor agonists (Sato et al., 2004).

In a double knockout, where mice lacked both mGlu2 and mGlu3, it was reported that appetitively-motivated spatial reference and working memory performances were impaired, whereas performance aversely-motivated spatial tasks were unaffected (Lyon et al., 2011b). The authors speculated that these differences may arise from a relatively greater degree of motivation in aversely-motivated tasks that allow the animals to overcome spatial learning deficits. In line with this, stress improved learning performance in the knock-outs. These data suggest that differences in behavioural results reported in other studies may be explained by relative differences in motivation and arousal in the animals. It suggests also, the role of group II mGlu receptors in this type of memory processing may only become salient in situations where high levels of motivation are not required.

6. Role of group III mGlu receptors in spatial memory

Most studies on the role of group III mGlu receptors in memory have been done using general antagonists of the receptor group. That is to say, receptor —specific antagonists have not been used. For example, (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), prevented reference memory in a radial maze and left working memory intact. Effects were associated with an impairment of LTD but not LTP in the CA1 region (Altinbilek and Manahan-Vaughan, 2007) and the dentate gyrus (Klausnitzer et al., 2004). CPPG also reduced habitation to complex odor-driven behavior (Yadon and Wilson, 2005), although a hippocampal contribution to this type of learning is unclear.

One group examined learning and memory in mice lacking mGlu7 (Holscher et al., 2004, 2005). Here, a selective effect on working memory in a battery of tests including a 4- and an 8-arm radial maze and spatial alternation task was observed. Reference memory remained intact. Effects were associated with increases in hippocampal theta rhythm. The authors speculate that increased theta could disturb working memory by altering spike timing and the temporal ordering of spikes. In line with this possibility, another study reported that both short-term potentiation and frequency facilitation is attenuated in mice lacking mGlu7 (Bushell et al., 2002).

Studies in mice lacking mGlu4 revealed no alterations in reference memory performance in the water maze (Gerlai et al., 1998). Curiously, in a spatial reversal learning task, a significantly accelerated learning performance was evident in the knock-outs, although 6 weeks after conclusion of the training they exhibited less precision in their ability to remember the location of the platform. Group III mGlu receptors are localised to the perforant path (Ohishi et al., 1995; Saugstad et al., 1994), which comprises the main input of the entorhinal cortex to hippocampus. The deficits in long-term memory revealed in the mGlu4 knock-puts may reflect impaired information flow from the entorhinal cortex to the hippocampus and thus signify importance for these receptors in this function.

7. Synthesis

Group I receptors appear to be equally important for both LTP and LTD (Manahan-Vaughan, 1997; Anwyl, 1999; Ayala et al., 2007;

Bellone et al., 2008; Kullmann and Lamsa, 2008). Group I mGlu receptors are principally post-synaptically localized. Activation of these receptors leads to cell depolarization, mainly by inhibiting potassium channel-mediated hyperpolarizations, thus action potentials are continuously generated throughout the depolarizing input (Coutinho and Knöpfel, 2002). MGlul exerts a much greater effect on calcium signaling mediated by the 1P3 pathway (Mannaioni et al., 2001) whereas mGlu5 activates somatic calcium transients, thereby modulating frequency accommodation in hippocampal synapses (Niswender and Conn, 2010). Presynaptically located group 1 mGlu receptors also exert negative effects on postsynaptic mechanisms by reducing glutamate transmission (Manzoni and Bockaert, 1995). This is a property that may be permissive towards LTD. Postsynaptic group 1 mGlus also modulate presynaptic neurotrans-mitter release by regulating retrograde messengers such as endo-cannabinoids (Niswender and Conn, 2010). As mentioned in Section 2.2.1 the contribution of group 1 mGlu receptors to persistent synaptic plasticity is protein synthesis and frequency-dependent (Harney et al., 2006; Naie et al., 2007; Neymann and Manahan-Vaughan, 2008) as is synaptic plasticity itself. The incoming afferent frequency is most likely the decisive factor in determining the direction of change in synaptic weight. The contribution of group 1 mGlus to this change may be driven by the relative saliency of this information (Wilsch et al., 2008) and the degree of activation of the receptors is likely to determine to what extent specific mGlu-coupled intracellular mechanisms and specific newly-synthesised proteins contribute to this phenomenon. Competition between mGlu5 and NMDARs may drive the bidirectionality of synaptic responses to afferent stimulation (Hsu et al., 2011) and thus explain why group 1 mGlus are equally important for both LTP and LTD.

Group 11 and group 111 mGlu receptors mainly attenuate excitatory transmission, largely due to their localisation to pre-synaptic membranes. These autoreceptors reduce transmitter release by inhibiting pre-synaptic voltage-dependent Ca2+ channels, which in turn suppress the transient Ca2+ current during invasion of a terminal by an action potential, thereby reducing transmitter release (Giustizieri et al., 2005; von Gersdorff et al., 1997). Presynaptic Group 11 and group 111 mGlu receptors also reduce GABA release from inhibitory terminals (Poncer et al., 1995; Salt et al., 1999). This may explain some of the more metaplastic effects that occur following activation of these receptors i.e. where LTD is facilitated or LTP is inhibited although no ostensible change in basal synaptic transmission was evident in control animals that received the agonist in the absence of an attempt to induce plasticity. Some of these receptors are also found postsynaptically where they can induce hyperpolarization (Muly et al., 2007): this may also contribute to the elevation of LTP thresholds mediated by activation of the receptors.

MGlu receptors regulate all forms of hippocampal learning that have been studied to date. Group 1 mGlus are critically required for both persistent LTP and LTD, and also contribute importantly to the maintenance of long-term memory (Balschun et al., 2002; Naie and Manahan-Vaughan, 2004, 2005; Simonyi et al., 2007). Learning-facilitated synaptic plasticity also requires activation of group 1 mGlus (Popkirov and Manahan-Vaughan, 2011) as do theta-gamma oscillations in the hippocampus (Bikbaev et al., 2008). 1ntriguingly, group 11 and 11 mGlu receptors, that are critically required for LTD but not LTP, appear to be highly important for long-term spatial memory (Holscher et al., 2004, 2005; Altinbilek and Manahan-Vaughan, 2009) that is linked to motivation (Lyon et al., 2011b). Given recent reports of a role for LTD in spatial context learning (Kemp and Manahan-Vaughan, 2007), these observations should open up new avenues in the development of strategies to address brain diseases that relate to deficits in spatial or hippocampus-dependent long-term memory.

8. Conclusions

In the past several years, substantial progress have been made in the research of the role of mGlu receptors in learning and memory. Data suggest that the involvement of mGlu receptors in hippocampal-dependent learning depends on the task and its relationship to synaptic plasticity. In line with this, electro-physiological data support a critical role for mGlu receptors in persistent forms of hippocampus-dependent synaptic plasticity, that are in turn believed to be essential for long-term information storage and memory. A pattern has emerged that supports that group II and group III mGlu receptors may be less important for the regulation of LTP, but highly significant for the regulation of persistent LTD and long-term spatial memory. In contrast, group I mGlu receptors are critically involved in both persistent LTP and LTD and in a multitude of hippocampus-dependent forms of memory. In line with this, dysfunctions in mGlu receptors are tightly associated with memory-impairing brain diseases that are characterized by disturbed synaptic plasticity (Huber et al., 2002; Bear et al., 2004; Merlin et al., 1998), or by neuronal pathologies that are associated with chronic changes in synaptic strength (Neugebauer et al., 2003; Derjean et al., 2003; Tappe et al., 2006).

MGlu receptors exert their influence not only by initiating signaling cascades that lead to stabilization of synaptic plasticity, they also strongly influence the induction phases of synaptic plasticity, by, for example, regulating the permeability of NMDA receptors (Mannaioni and Conn, 2001). Evidence also exists that they influence protein—protein interactions within the synaptic scaffold, thus optimizing or altering communication across and within the synapses (Binns and Salt, 2001; Enz, 2002; Bockaert et al., 2010) and regulate neuronal information transfer (Bikbaev et al., 2008). Taken, together these findings suggest that the significance of mGlu receptors in brain function related to information storage and plasticity should not be underestimated. This family of receptors may hold the key to the longevity and stability of synaptic plasticity underlying long-term memory.

Conflicting interests

The authors have declared that no conflicting interests exist.

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