Selective mGlu 1 potentiation enhances cortical inhibition to rescue schizophrenia‐like cognitive and social deficits

Abstract

Accumulating evidence suggests that selective activators of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor may provide a promising novel therapeutic approach for the treatment of schizophrenia. Genetic studies in humans reveal an association of the human gene encoding mGlu1 (GRM1) and, specifically, loss of function single nucleotide polymorphisms in GRM1 with schizophrenia, raising the possibility that mGlu1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder. Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying behavioral deficits in schizophrenia patients, including cognitive and social impairment. This is especially interesting in light of our recent studies demonstrating that activation of mGlu1 increases inhibitory transmission in the PFC by selective excitation of somatostatin-expressing GABA interneurons. Here, we leverage recently developed positive allosteric modulators (PAMs) selective for mGlu1 to examine whether mGlu1 activation might reverse electrophysiological effects and behavioral deficits induced by MK-801, an NMDA receptor antagonist commonly used to model cortical pathophysiology relevant to behavioral and cognitive deficits observed in schizophrenia patients. Using ex vivo whole-cell patch-clamp electrophysiology, we found that MK-801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC and this cortical disinhibition was reversed by mGlu1 activation, suggesting that mGlu1 activation is a pertinent mechanism to restore inhibitory signaling in the PFC. Importantly, the mGlu1 PAM VU6004909 effectively reversed MK-801-induced deficits in working memory as measured by spontaneous alternation in a Y-maze task and restored social interaction in a three-chamber assay. In combination with our previous reports that mGlu1 PAMs possess potential antipsychotic-like efficacy and reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence that mGlu1 PAMs could serve as a novel approach that could reduce positive symptoms and also treat cognitive and social deficits in schizophrenia patients, providing an exciting improvement over current antipsychotics.