In the hippocampal CA1 region, metabotropic glutamate subtype 1 (mGluR1) receptors have been implicated in a variety of physiological responses to glutamate, which include modulation of synaptic transmission and plasticity, as well as neuronal excitability and synchronization. The mGluR1alpha isoform is characteristically expressed only by nonprincipal cells, and it is particularly enriched in somatostatin (SS)-containing interneurons in stratum oriensalveus. Anatomical and physiological data have indicated the presence of mGluR1alpha in several distinct classes of interneurons with their somata located also in strata pyramidale, radiatum, and lacunosum moleculare. Each different interneuron subtype, as defined by functionally relevant criteria, including input/ output characteristics and expression of selective molecular markers, subserves distinct functions in local hippocampal circuits. We have investigated which of the different CA1 interneuron classes express mGluR1alpha by immunofluorescent labeling, combining antibodies to mGluR1alpha, calcium-binding proteins, and neuropeptides, and by intracellular labeling in vitro. Several types of interneuron that are immunopositive for mGluR1alpha each targeted different domains of pyramidal cells and included (1) O-LM inter-neurons, found to coexpress both SS and parvalbumin (PV); (2) interneurons with target selectivity for other interneurons, expressing vasoactive intestinal polypeptide (VIP) and/or the calcium-binding protein calretinin; (3) procholecystokinin-immunopositive interneurons probably non-basket and dendrite-targeting; and (4) an as-yet unidentified SS-immunoreactive but PV-immunonegative interneuron class, possibly corresponding to oriens-bistratified cells. Estimation of the relative proportion of mGluR1alpha-positive interneurons showed 43%, 46%, and 30% co-labeling with SS, VIP, or PV, respectively. The identification of the specific subclasses of CA1 interneurons expressing mGluR1alpha provides the network basis for assessing the contribution of this receptor to the excitability of the hippocampus.

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To examine the involvement of different ionotropic glutamate receptors in the mediation of responses evoked by noxious cutaneous stimulation, single unit recordings were made from 31 neurons in the primary somatosensory (SI) cortex of rats anesthetized with urethane. To compare synaptic receptor pharmacology across somatosensory submodalities, 13 of the neurons were also tested with an innocuous, cutaneous air jet stimulus. Mechanical (HT) responses, evoked by a 5-s noxious pinch, decayed gradually upon termination of the stimulus and lasted on average for 15.1+/-1.9 s (+/-SEM; n=10). An increase in baseline activity was also observed during noxious stimulus trials of 5-min stimulus intervals. A correlation between increase in mechanical or thermal HT responses and baseline activity was found for some neurons. However, the normalized ratios of the mechanical or thermal HT response to baseline activity during iontophoretic application of (RS)-3-(2-carboxypiperazine-4-yl)-propyl-l-phosphonic acid (CPP), an N-methyl-D-aspartic acid (NMDA) receptor antagonist (0.6+/-0.1; n=11, or 6-nitro-7-sulfamoylbenz[f]quinoxaline-2,3-dione (NBQX), an (RS)-alpha-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist (0.8+/-0.1; n=11), suggest that the reductions in baseline activity did not account for the reductions of the mechanical or thermal HT responses observed, which were reduced proportionally more than the baseline activity. A 10-ms air jet evoked a biphasic increase in action potentials above an average background activity of 7+/-2 spikes/s (n=13). The early phase of this low-threshold (LT) response was within two or three 10-ms bins and had an average firing rate of 74+/-11 spikes/s evoked in the first 10-ms bin (n=13). In eight neurons, the early LT response was followed by a lower frequency excitatory component lasting an average of 415+/-92 ms. Iontophoretic application of CPP reduced responses evoked by a noxious pinch (21+/-10% of control responses; n=19) and a noxious thermal stimulus (24+/-18%; n=5). The fast component of the LT responses was only reduced to 85+/-4% (n=12). A slower component of the LT responses, when present, was also reduced by CPP (15+/-19%; n=4). Iontophoretic application of NBQX reduced responses evoked by a noxious pinch (42+/-12%; n=19) and a noxious thermal stimulus (63+/-16%; n=8). The fast component of the LT responses was reduced to 43+/-6% (n=12) and the slower component to 32+/-20% (n=6). These data show that both NMDA and AMPA/kainate receptors are involved in the mediation of SI high-threshold responses. This same combination of glutamate receptors also mediates low-threshold synaptic responses.

Suppressing anxiety and fear memory relies on bidirectional projections between the medial prefrontal cortex and the amygdala. Positive allosteric modulators of mGluR5 improve cognition in animal models of schizophrenia and retrieval of newly formed associations such as extinction of fear-conditioned behaviour. The increase in neuronal network activities of the medial prefrontal cortex is influenced by both mGluR1 and mGluR5; however, it is not well understood how they modulate network activities and downstream information processing. To map mGluR5-mediated network activity in relation to its emergence as a viable cognitive enhancer, we tested group I mGluR compounds on medial prefrontal cortex network activity via multielectrode array neuronal spiking and whole-cell patch clamp recordings. Results indicate that mGluR5 activation promotes feed-forward inhibition that depends on recruitment of neuronal activity by carbachol-evoked up states. The rate of neuronal spiking activity under the influence of carbachol was reduced by the mGluR5 positive allosteric modulator, N-(1,3-Diphenyl-1H-pyrazolo-5-yl)-4-nitrobenzamide (VU-29), and enhanced by the mGluR5 negative allosteric modulator, 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP). Spontaneous inhibitory post-synaptic currents were increased upon application of carbachol and in combination with VU-29. These results emphasize a bias towards tonic mGluR5-mediated inhibition that might serve as a signal-to-noise enhancer of sensory inputs projected from associated limbic areas onto the medial prefrontal cortex neuronal microcircuit. Reprints and permissions: sagepub.co.uk/journalsPermissions.nav