The activation of group I metabotropic glutamate receptors (mGluRs) produces a variety of actions that lead to alterations in excitability and synaptic transmission in the CA1 region of the hippocampus. The group I mGluRs, mGluR1 and mGluR5, are activated selectively by (S)-3,5-dihydroxyphenylglycine (DHPG). To identify which of these mGluR subtypes are responsible for the various actions of DHPG in area CA1, we took advantage of two novel subtype-selective antagonists. (S)-(ϩ)-␣-amino-a-methylbenzeneacetic acid (LY367385) is a potent competitive antagonist that is selective for mGluR1, whereas 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is a potent noncompetitive antagonist that is selective for mGluR5. The use of these compounds in experiments with whole-cell patch-clamp recording and Ca 2ϩ -imaging techniques revealed that each group I mGluR subtype plays distinct roles in regulating the function of CA1 pyramidal neurons. The block of mGluR1 by LY367385 suppressed the DHPG-induced increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and the direct depolarization of CA1 hippocampal neurons. In addition, the increase in the frequency of spontaneous IPSCs (sIPSCs) caused by the DHPG-induced depolarization of inhibitory interneurons also was blocked by LY367385, as was the DHPG-induced inhibition of transmission at the Schaffer collateral3CA1 synapse. On the other hand, the block of mGluR5 by MPEP antagonized the DHPG-induced suppression of the Ca 2ϩ -activated potassium current (I AHP ) and potentiation of the NMDA receptor. Finally, antagonism of the DHPG-induced suppression of evoked IPSCs required the blockade of both mGluR1 and mGluR5. These data suggest that mGluR1 and mGluR5 play distinct roles in the regulation of the excitability of hippocampal CA1 pyramidal neurons. Key words: mGluR; mGluR1; mGluR5; (S)-3,5-dihydroxyphenylglycine (DHPG); (S)-(ϩ)-␣-amino-a-methylbenzeneacetic acid (LY367385); 2-methyl-6-(phenylethynyl)-pyridine (MPEP); I AHP ; IPSC; EPSC; hippocampusMetabotropic glutamate receptors (mGluRs) have been implicated in a number of physiological and pathological responses to glutamate in CA1 hippocampal region. These include the modulation of neuronal excitability and synaptic transmission (for review, see Anwyl, 1999) as well as the induction of long-term potentiation (Bashir et al., 1993), generation of epileptiform activity (Aronica et al

In recent years there have been tremendous advances in our understanding of the circuitry of the basal ganglia and our ability to predict the behavioural effects of specific cellular changes in this circuit on voluntary movement. These advances, combined with a new understanding of the rich distribution and diverse physiological roles of metabotropic glutamate receptors in the basal ganglia, indicate that these receptors might have a key role in motor control and raise the exciting possibility that they might provide therapeutic targets for the treatment of Parkinson's disease and related disorders.

Parkinson's disease (PD) is a debilitating movement disorder that afflicts >1 million people in North America. Current treatments focused on dopamine-replacement strategies ultimately fail in most patients because of loss of efficacy and severe adverse effects that worsen as the disease progresses. The recent success of surgical approaches suggests that a pharmacological intervention that bypasses the dopamine system and restores balance in the basal ganglia motor circuit may provide an effective treatment strategy. We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD. We now report that N-phenyl-7-(hydroxylimino)cyclopropa[b]-chromen-1a-carboxamide (PHCCC) is a selective allosteric potentiator of mGluR4. This compound selectively potentiated agonistinduced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist. Furthermore, PHCCC potentiated the effect of L-(؉)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. Modulation of the striatopallidal synapse has been proposed as a potential therapeutic target for PD, in that it may restore balance in the basal ganglia motor circuit. Consistent with this, PHCCC produced a marked reversal of reserpine-induced akinesia in rats. The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model. These results are evidence for in vivo behavioral effects of an allosteric potentiator of mGluRs and suggest that potentiation of mGluR4 may be a useful therapeutic approach to the treatment of PD. P arkinson's disease (PD) is a debilitating neurodegenerative disorder that afflicts Ϸ1% of people older than 55 years. The primary pathology underlying PD is a degeneration of neurons in the substantia nigra pars compacta (1). The finding that these neurons are dopaminergic cells that provide a dense innervation of the striatum (2) led to the development of dopaminereplacement therapies for the treatment of this disease. Drugs such as the dopamine precursor L-dopa and dopamine receptor agonists provide dramatic amelioration of the motor signs of PD at early stages of the disease. However, prolonged treatment with these drugs leads to a loss of reliable efficacy and a variety of motor and cognitive side effects (3). In addition, disagreement still exists as to whether or not L-dopa therapy may actually speed disease progression through increased oxidative damage (for review, see refs. 4 and 5). Therefore, interest has been renewed in the design of therapeutic methods that bypass the dopamine system.One such method has been suggested by the recent resurgence and advances in surgical interventions such as pallidotomy or deep-brain stimulation. These approaches have led to both dramatic palliative benefits for PD patients and an unprecedented refinement of the model of basal ganglia dysfunct...

Evidence suggests that cholinergic input to the hippocampus plays an important role in learning and memory and that degeneration of cholinergic terminals in the hippocampus may contribute to the memory loss associated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists. Here, we employ traditional pharmacological reagents as well as m1-toxin, an m1 antagonist with unprecedented selectivity, to demonstrate that this potentiation of NMDA-receptor currents in hippocampal CA1 pyramidal cells is mediated by the genetically defined m1 muscarinic receptor. Furthermore, we demonstrate the colocalization of the m1 muscarinic receptor and the NR1a NMDA receptor subunit at the electron microscopic level, indicating a spatial relationship that would allow for physiological interactions between these two receptors. This work demonstrates that the m1-muscarinic receptor gene product modulates excitatory synaptic transmission, and it has important implications in the study of learning and memory as well as the design of drugs to treat neurodegenerative diseases such as Alzheimer's.One of the major neuromodulatory inputs to the hippocampus is a large cholinergic projection from the medial septum and the diagonal band of Broca (1). Both animal and human studies indicate that cholinergic modulation of hippocampal and cortical function plays an important role in memory and attention (2-7). Furthermore, abundant evidence suggests that the clinical syndrome associated with Alzheimer's disease results, at least in part, from the degeneration of basal forebrain cholinergic neurons and the resulting depletion of cholinergic markers in neocortex and hippocampus (8-12). Because of this, a great deal of effort has been focused on determining the cellular mechanisms involved in cholinergic modulation of hippocampal function and the specific acetylcholine (ACh) receptor subtypes that mediate these responses.One of the predominant effects of cholinergic agonists on hippocampal CA1 neurons is potentiation of currents through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (NMDAR) (13-16). The NMDAR plays a pivotal role in long-lasting forms of synaptic plasticity thought to underlie learning and memory (17). Thus, potentiation of NMDAR currents (I NMDA ) could provide a crucial mechanism by which cholinergic input to the hippocampus modulates memory and attention. In addition, the cholinergic receptor that mediates this potentiation could provide a target for the development of drugs to treat memory disorders (e.g., Alzheimer's disease).Evidence suggests that ACh-induced potentiation of NMDAR currents is mediated by muscarinic ACh receptors (mAChRs) (14). However, the specific mAChR subtype that mediates this response is not known. The mAChRs have been classified into m1-m5 subtypes based on molecular analysis of genes that encode five highly related but structurally distin...