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 metabotropic glutamate 1 (mGlu1) receptor, a subtype of the mGlu receptor family, is a promising therapeutic target because its activation enhances inhibitory transmission in the PFC through the excitation of somatostatin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (SST-INs).

Methods: We used a subchronic phencyclidine (PCP) NMDA receptor antagonist mouse model, mGlu1 positive allosteric modulators (PAMs), and mice with selective deletion of mGlu1 receptors from SST-INs to examine the cell type–specific role of mGlu1 signaling in cortical inhibition and cognition. We used ex vivo whole-cell patch-clamp electrophysiology 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 mGlu1 restored inhibitory drive and reversed PCP-induced deficits in working memory and novel object recognition. Importantly, selective deletion of mGlu1 receptors from SST-INs abolished the ability of mGlu1 activation to restore cortical inhibition and cognitive function, demonstrating that these receptors are required for the therapeutic effects of mGlu1 PAMs.

Conclusions: These findings identify SST-IN–expressed mGlu1 receptors as critical regulators of prefrontal cortical inhibition and cognition. Positive allosteric modulation of mGlu1 represents a promising therapeutic strategy for treating cognitive deficits associated with schizophrenia by restoring inhibitory circuit function.