Metabotropic Glutamate Receptors

Whereas the ionotropic glutamate receptors are capable of secondarily directly or indirectly activating mechanisms of synaptic plasticity, the metabotropic receptors are directly coupled to second-messenger pathways that mediate forms of short-term plasticity. There are at least eight cloned metabotropic glutamate receptors (termed mGluR1-mGluR8) (4). These have been classified into three groups based on sequence homology, coupling to second-messenger systems, and pharmacological sensitivities. Group I receptors are coupled to phosphoinositide (PI) hydrolysis that leads to Ca2+ mobilization from intracellu-lar stores, whereas groups II and III receptors are negatively coupled to adenylyl cyclase (AC) activity.

Although the consequences of metabotropic glutamate receptor activation vary depending on receptor type, neuronal type, or brain region, some general principles regarding the outcomes of their activation have emerged (5). Postsynaptic group I metabotropic receptor activation, in general, causes and increase in the intrinsic excitability of principal neurons (particularly in hippocampal CA1 and CA3 subfields), mainly via down-modulation of voltage-gated potassium channels (50), groups II and III receptor activation tends to depress excitatory synaptic transmission by inhibiting glutamate release (51).

Evidence suggests that group I postsynaptic metabotropic glutamate receptors are mostly involved in the regulation of synaptic plasticity (for reviews, see refs. 52 and 53). For example, mice lacking mGluR5 show reduced hippocampal CA1 LTP (although CA3 LTP was normal) (54). However, presynaptic metabotropic glutamate receptors also may play roles in synaptic plasticity, as Laezza et al. showed that LTD in CA3 interneurons only resulted from a synergistic effect that required both the activation of presynaptic metabotropic receptors and Ca2+ entry through postsynaptic AMPA receptors (36). Thus, either presynaptic or postsynaptic metabotropic glutamate receptors may contribute to glu-tamate-mediated synaptic plasticity under different conditions.

Interestingly, in the developing brain, as with the ionotropic glutamate receptors, metabotropic glutamate receptor function undergoes maturational regulation in such a manner as to promote neuronal excitability in early postnatal development. Agonist-stimulated PI turnover has been shown to be relatively robust in slices of immature rat brain, increasing from age P1 to P7-P10 before gradually decreasing to adult levels at around P24 (55). This contrasts with the activity of metabotropic receptors negatively coupled to AC, as cyclic AMP accumulation induced by the AC activator forskolin was shown to be inhibited by the nonspecific metabotropic glutamate receptor agonist 1S,3,R(ACPD) in adult but not in neonatal (P1-P15) rat hippocampus (56,57). Notably, metabotropic glutamate receptors negatively coupled to AC are expressed in early postnatal development, but nonspecific metabotropic receptor activation in the neonatal hippocampus increases basal cyclic AMP levels (58) and, thus, would be expected to promote neuronal excitability in early postnatal development. Consistent with notion, the nonspecific mGluR agonist 1S,3,R-1-aminocyclopentane-1,3,dicarboxylic acid [(1S,3,R)ACPD], which activates both AC- and PI-coupled metabotropic receptors, was shown to elicit dose- dependent limbic seizures in neonatal (postnatal d 7) rats (59). This proconvulsant effect was similar to that observed for the specific group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG) (60), suggesting that it was mediated by AC-coupled metabotropic receptors. Furthermore, specific group II agonists appear to be anticonvulsants intraventricular infusion of the group II agonist (2S,1'R,2',R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) decreased the incidence of continuous limbic motor seizures induced by intraventricular kainate (61), and microinjection of (S)-4-carboxy-3-hydroxyphenylglycine ](S)-4C3HPG], a group I antagonist and group II agonist, into the inferior colliculus inhibited audiogenic seizures in genetically epilepsy-prone rats (62). However, the proconvulsant actions of nonspecific metabotropic glutamate receptor agonists may not be entirely age-selective, as microinjections of (1S,3^)ACPD in adult rat hippocampus (63) also elicited limbic seizures. Compared to the ionotropic glutamate receptors, the developmental pattern of metabotropic glutamate receptor function is not as clearly linked to the developmental patterns of mGluR gene expression and glutamate receptor-mediated pathogenesis.

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