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Selective mGlu 1 potentiation enhances cortical inhibition to rescue schizophrenia‐like cognitive and social deficits
Author(s) -
Luessen Deborah,
Gallinger Isabel,
Maksymetz James,
Conn P.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01793
Subject(s) - neuroscience , inhibitory postsynaptic potential , metabotropic glutamate receptor , disinhibition , nmda receptor , long term potentiation , prefrontal cortex , glutamate receptor , schizophrenia (object oriented programming) , psychology , neurotransmission , biology , cognition , receptor , psychiatry , genetics
Accumulating evidence suggests that selective activators of the mGlu 1 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 mGlu 1 ( GRM1 ) and, specifically, loss of function single nucleotide polymorphisms in GRM1 with schizophrenia, raising the possibility that mGlu 1 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 mGlu 1 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 mGlu 1 to examine whether mGlu 1 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 mGlu 1 activation, suggesting that mGlu 1 activation is a pertinent mechanism to restore inhibitory signaling in the PFC. Importantly, the mGlu 1 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 mGlu 1 PAMs possess potential antipsychotic‐like efficacy and reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence that mGlu 1 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.