Metabotropic glutamate receptor activation and blockade: their role in long-term potentiation, learning and neurotoxicity

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Abstract

Metabotropic glutamate receptors represent a fairly recent addition to the family of glutamate receptors. These receptors have the distinguishing feature of being coupled to G-proteins rather than ion channels and they appear to have a variety of functional characteristics. These receptors play a vital role, for example, in the induction and maintenance of long-term potentiation, the most popular current model of the biological correlates of learning and memory. Blockade of metabotropic glutamate receptors prevents long-term potentiation induction and learning in a variety of tasks in different species. Chronic metabotropic glutamate receptor activation is also associated with neurodegeneration and selective neuronal loss when agonists of these receptors are injected in high concentrations directly into the brain. Metabotropic glutamate receptors also play a role in the normal development of the nervous system and these sites within the central nervous system offer possible routes for drug therapies; selective receptor antagonists, for example, may prove to have the very desirable feature of endowing neuroprotection during ischaemic episodes whilst allowing normal excitatory neurotransmission to occur.

Introduction

Glutamate is the primary excitatory neurotransmitter implicated in synaptic transmission in the hippocampus and cerebral cortex. The role of glutamate in both long-term potentiation (LTP) and learning and memory has been extensively examined in many laboratories over the past 20 years [9], [8].

Glutamate is released from presynaptic terminals and diffuses across the synaptic cleft where it binds to postsynaptic glutamate receptor subtypes (Fig. 1). Various studies have indicated that glutamate receptors occur in two major sub-types: ionotropic (with an associated intrinsic ion channel) and metabotropic (with an intrinsic membrane-spanning protein coupled to various second messenger systems). The general features of these two sub-types are reviewed below. Glutamate also binds to presynaptic autoreceptors where it may regulate the release of the neurotransmitter itself, depending on whether autoreceptor activation is negatively or positively coupled to transmitter release.

The ionotropic family of glutamate receptors is usually subdivided into two major categories: the N-methyl-d-aspartate (NMDA) receptor-gated Ca2+ channel and the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor [8] (Fig. 1). Activation of the AMPA receptor causes depolarisation of the postsynaptic terminal. This action allows the AMPA receptors to perform `fast' synaptic transmission in the central nervous system. Activation of the NMDA receptor ion channel requires that the postsynaptic neuron be strongly depolarised; when the NMDA receptor-coupled ion channel opens, calcium is admitted into the cell where it may activate a variety of intracellular processes. It has been speculated that this surge in intracellular calcium levels leads to the phosphorylation of calcium/calmodulin dependent kinases and to long-term potentiation (LTP) of synaptic transmission [54], [8] (see below for a description of LTP). If this `surge' in postsynaptic calcium levels is not regulated, neuronal death may occur via a process termed excitotoxicity [111]. It is thought that intense activation of ionotropic receptors such as the NMDA receptor may mediate acute excitotoxic events such as may occur in cerebrovascular accident (stroke) and the focal and diffuse brain lesions resulting from head trauma [72]. The chronic elevation of NMDA receptor activity has been indicated in a number of neurological disorders, including neurodegenerative states such as Parkinson's disease and Huntington's chorea [111]; one possible treatment for these conditions may be the administration of agents that act at mGluRs [81]. Many studies have indicated that the NMDA receptor subtype is also critically involved in the induction of LTP-blockade of this receptor with the drug 2-amino-5-phosphonovaleric acid (AP5) blocks LTP induction [8]. Furthermore, NMDA receptor activation appears to be necessary for at least some forms of learning-blockade of the NMDA receptor in vivo blocks spatial learning in rats in the water maze [69], [4] at tissue concentrations similar to those which block LTP in vitro. Blockade of the AMPA receptor subtype does not prevent LTP induction [35]. The role of glutamate and other excitatory amino acids in synaptic transmission in the nervous system has been reviewed extensively by Collingridge and Lester [22].

The metabotropic glutamate receptor (mGluR) is a G-protein linked glutamate sensitive receptor [10] (see Fig. 1) that acts to control the activity of membrane enzymes and ion channels [101]. In contrast to ionotropic glutamate receptors, much less is known about the role of the metabotropic glutamate receptor in either normal synaptic transmission, LTP, learning or development.

At least eight subtypes of the postsynaptic receptor have been identified to date [116], [104], [27] these differ depending on the second messenger system involved and the identity of agonist they are sensitive to (Fig. 1, Table 1Table 2Table 3). The mGluRs can be subdivided into three groups (see Table 1, Table 2, Table 3): group I includes mGluR1 and mGluR5; group II includes mGluR2 and mGluR3; and group III includes mGluR4, mGluR6, mGluR7, and mGluR8. Activation of group I mGluRs increases neuronal excitation whereas activation of group II and group III mGluRs tends to decrease excitation. In the hippocampus, mGluR group I are predominately expressed postsynaptically while mGluRs group II and III are found presynapticallywhere they reduce transmitter release as autoreceptors [112]. The mGluRs group I are coupled to phosphoinositide (PI) hydrolysis and also increase cAMP via indirect mechanisms. Group II and III mGluRs inhibit adenylyl cyclase and reduce cyclic AMP (cAMP) synthesis [106]. Downregulation of cAMP production via activation of mGluRs suggests that there should be a diminution of signalling and thus inhibition of synaptic transmission. The hydrolysis of PI ultimately leads to the release of calcium from intracellular stores [30] and then possibly to other processes related to a rise in intracellular calcium such as protein kinase C activation. The presynaptic mGluR may upregulate or downregulate neurotransmitter release, depending on whether or not the mGluR autoreceptor is positively or negatively coupled to glutamate exocytosis; there may therefore be an involvement of this receptor in LTP (perhaps via an increase in glutamate release) or long-term depression (possibly via a decrease in glutamate release). Recent evidence has suggested that mGluRs may also activate inwardly rectifying potassium channels to produce presynaptic and/or postsynaptic inhibition [102].

The hippocampus is perhaps the most intensively studied region of the mammalian brain today, in part due to its relatively simple synaptic structure and important role in learning and memory (see below). Most current studies into synaptic transmission use the hippocampus as a substrate. As the hippocampus is a widely studied area and has relatively high levels of mGluRs distributed throughout all its subfields [112], it follows that most of our current knowledge regarding the function of mGluRs derives from hippocampal studies. A recent study of the anatomical distribution of different mGluR subtypes in the hippocampus showed a differentiated expression of subtypes in its subareas. Immunoreactivity for mGluR5 and mGluR7a is distributed in all dendritic layers throughout the hippocampus, whereas immunoreactivity for the other mGluRs is restricted to distinct regions. Immunoreactivity for mGluR1 is strong in dendritic fields of the dentate gyrus (DG) and CA3, as well as in the CA1 stratum oriens/alveus border. Immunoreactivity for mGluR2/3 is strong in terminal zones of the perforant path and mossy fibres, whereas that for mGluR7b is restricted to the mossy fibre terminal zone, and that for mGluR8 to the lateral perforant path terminal zone, i.e. the outer third of the dentate molecular layer and outer layer of CA3 stratum lacunosum moleculare. Immunoreactivity for mGluR4a is weak but prominent in the inner third of the molecular layer. Labelling for mGluR6 is absent in the hippocampus [113]. In the visual cortex the expression of mGluRs is layer specific [83], so drugs can have opposite effects on evoked neuronal firing depending upon the particular cell layer the recording is from [82].

The recent development of selective agonists and antagonists to mGluRs has greatly facilitated investigations into the role of mGluRs in synaptic transmission [48]. There are currently several selective agonists and antagonists available (Table 1, Table 2, Table 3). The most frequently used agonists are: (a) 1S,3R-1-amino-cyclo-pentyl-1,3-dicarboxylic acid (1S,3R-ACPD) which acts preferentially at group II mGluRs (5 μM EC; Table 1, Table 2, Table 3), with somewhat less affinity at group I mGluRs (50 μM EC) and no affinity to group III mGluRs [47], [79]; and (b) l-2-amino-4-phosphonobutanoic acid (l-AP4) which appears to be a specific agonist for mGluRs 4, 6, 7 and 8 [71], [97], [99]. Furthermore, a different mGluR that facilitates synaptic transmission exists that has not been cloned yet but appears to be related to mGluR8. Unusually, it is sensitive to l-AP4 and 1S,3R-ACPD (just like mGluR8 [98]) and facilitates glutamate transmission when activated [38], [39].

Historically, the most widely used selective antagonist for mGluRs has been (±)alpha-methyl-4-carboxyphenylglycine (MCPG; Table 1, Table 2, Table 3). MCPG is currently considered to be a non-selective mGluR antagonist and may even act as a partial agonist. More selective agents would include α-methyl-(2S,3S,4S)-α-(carboxycyclopropyl)glycine (MCCG), (RS)-α-methyl-4-tetrazolylphenylglycine (MTPG) and α-methyl-l-2-amino-4-phosphonobutyrate (MAP4) [48], [49] (see Table 1, Table 2, Table 3 for details).

The most popular current model for the biological substrates of learning and memory in the mammalian brain is that of long-term potentiation (LTP) [8]. The role of glutamate receptor activation in LTP is currently under extensive investigation in a number of laboratories world-wide. LTP is commonly induced at glutamatergic synapses using high frequency electrical stimulation (`tetanisation'). LTP is most commonly studied in the hippocampus, especially in the dentate gyrus in vivo and in the CA1 subfield in vitro. LTP is usually measured as a persistent increase in the size of the evoked response from either a single cell (when recorded using either sharp or patch electrodes) or in a population of cells (when it is measured as an increase in the amplitude or slope of the extracellularly recorded evoked field excitatory post synaptic potential or EPSP). LTP has various properties that have made it an attractive model for the biological substrates of learning [9], [8]: it is long-lasting (from hours to days depending on the preparation used); it is input specific to a certain degree (only the tetanised synapses and some of the neigbouring synapses undergo potentiation, for details see [11]); and it is co-operative (although a certain number of presynaptic terminals must be activated in vivo in order to depolarise the postsynaptic neuron sufficiently so that it can undergo potentiation, single synaptic contacts appear to be sufficient in the slice preparation [59]).

In brief, LTP in are a CA1 of the hippocampus is assumed to be induced by activation of an AMPA-receptor-associated Na+ channel that is strong enough do cause membrane depolarisations that remove a Mg2+ block off a NMDA-receptor-associated Ca2+-channel. This causes the Ca2+-channel to open and allow Ca2+ to enter the postsynaptic neuron. Ca2+ acts as a second messenger that activates a number of kinases and lipases that are part of a biochemical cascade that consolidate LTP. An increase of transmitter release at the presynaptic site also contributes to LTP formation [8].

LTP is regarded as a cellular instantiation of the Hebb learning rule [37], [54], [8], because it involves a use-dependent increase in the strength of tetanised synapses.

Section snippets

Synaptic mechanisms

The majority of available studies into the role of mGluRs in synaptic transmission have been conducted using in vitro brain slice or cell culture preparations. Nonetheless, some useful inferences may be drawn from such work regarding the possible role of the mGluR in the intact brain. Activation or blockade of mGluRs has a number of effects on synaptic transmission. Activation of mGluRs may cause: (i) presynaptic inhibition of excitatory neurotransmission in the hippocampus [7] and visual

Conclusions

It is evident from the above review that mGluRs are implicated in a wide range of normal and pathological processes in brain function, both in the developing and adult nervous system. The emerging picture in LTP research using brain slices is that co-activation of NMDA and mGluRs is necessary for LTP induction. This also appears to be true in the intact animal. However, the precise relationship between these forms of LTP and learning is still unclear. Recent evidence even suggests that: (a)

Acknowledgments

CH has been supported by the Health Research Board of Ireland and by departmental funds; JG by an European Union TMR grant; and SMOM supported in part by the Wellcome Trust and the Trinity College Provost's Fund.

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