Selective mGlu₁ Receptor Activation Restores Cortical Inhibitory Tone and Improves Cognitive Performance in a...

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).

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.

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.

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.