Modulation of neuronal microcircuit activities within the medial prefrontal cortex by mGluR5 positive allosteric modulator

Abstract

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

Metabotropic glutamate 5 receptor in the infralimbic cortex contributes to descending pain facilitation in healthy and arthritic animals

“…A potential explanation for this finding is that the effect of mGluR5 activation triggers an inhibitory mechanism, leading to suppression of neuronal discharge in the IL. In line with this hypothesis, a recent study by Pollard et al (2014) has shown that mGluR5 activation leads to inhibition of neuronal activity in the ventral mPFC by promoting feed-forward inhibition. However, there are also contrasting reports that show mGluR5 activation in the ventral mPFC increases neuronal excitability by reducing the release of presynaptic GABA (Kiritoshi et al, 2013;Ji and Neugebauer, 2014).…”

mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex

“…Thus, although we observed no effects of treatment with CDPPB on spine density or morphology in the present study, it is possible that mGluR5 PAMs may alter dendritic spine density and morphology in pyramidal neurons in the mPFC either in the presence of other pharmacological manipulations or performance in behavioral tasks. Recent electrophysiological data support this notion, as local application of an mGluR5 PAM onto mPFC slices had no effect on pyramidal neuronal firing rates alone, but altered activity when combined with the cholinergic agonist carbachol [74]. However, other studies have demonstrated that acute mGluR5 PAM or orthosteric agonist administration increases mPFC spontaneous neuronal activity [75–78].…”

“…However, other studies have demonstrated that acute mGluR5 PAM or orthosteric agonist administration increases mPFC spontaneous neuronal activity [75–78]. It is also unclear as what regions other than the mPFC might demonstrate structural plasticity in response to repeated mGluR5 PAM or NAM administration, since the expression of mGluR5 receptors is high in other regions such as the striatum and hippocampus, and mGluR5 PAMs affect other measures of neuronal plasticity such as LTP and LTD in regions such as the hippocampus [21, 74]. Clearly, future studies incorporating other pharmacological manipulations or behavioral tasks are needed to determine under what conditions and brain regions mGluR5 PAMs are able to modulate dendritic spine density and/or morphology.…”

An Appraisal of the Influence of the Metabotropic Glutamate 5 (mGlu5) Receptor on Sociability and Anxiety

“…To understand at the anatomical level where mGlu5 receptors regulate brain activity during social exploration, we have analyzed the expression of c-Fos in a selected set of brain areas previously reported to be activated upon social interaction (Kim et al, 2015). Our study shows that in Grm5 -/- mice, MO, PrL, IL, and LSD were selectively activated upon interaction with a conspecific, suggesting that mGlu5 receptors dampen neuronal activity in these brain regions during social behavior, possibly by activating interneurons and facilitating feedforward inhibition (Pollard et al, 2014). Future studies will have to unveil the expression and role of mGlu5 receptors in the different neuronal types in these brain areas and their specific contribution to social behavior.…”