Selective mGlu1 Receptor Activation Restores Cortical Inhibitory Tone and Improves Cognitive Performance in a Subchronic Phencyclidine NMDA Hypofunction Model

Background Deficits in prefrontal cortex (PFC) inhibitory transmission are thought to underlie the cognitive symptoms of schizophrenia that remain untreated by current pharmacotherapies. The mGlu 1 subtype of metabotropic glutamate receptor is a promising therapeutic target because its activation enhances inhibitory transmission in the PFC through excitation of somatostatin-expressing GABAergic interneurons (SST-INs). Methods We used a subchronic phencyclidine (PCP) N-methyl-D-aspartate receptor antagonist mouse model, mGlu 1 positive allosteric modulators (PAMs), and mice with selective deletion of mGlu 1 receptors from SST-INs to examine the cell type-specific role of mGlu 1 signaling in cortical inhibition and cognition. Ex vivo whole-cell patch-clamp electrophysiology was used to assess inhibitory transmission in the PFC, and cognitive performance was evaluated using tests of working memory and novel object recognition. Results Subchronic PCP treatment impaired inhibitory synaptic transmission in the PFC, particularly onto layer V pyramidal neurons projecting to the nucleus accumbens. Pharmacological activation of mGlu 1 restored inhibitory drive and reversed PCP-induced deficits in working memory and novel object recognition. Importantly, selective deletion of mGlu 1 receptors from SST-INs abolished the ability of mGlu 1 activation to restore cortical inhibition and cognitive function, demonstrating that these receptors are required for the therapeutic effects of mGlu 1 PAMs. Conclusions These findings identify SST interneuron-expressed mGlu 1 receptors as critical regulators of prefrontal cortical inhibition and cognition. Positive allosteric modulation of mGlu 1 represents a promising therapeutic strategy for treating the cognitive deficits associated with schizophrenia by restoring inhibitory circuit function.