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.