Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

Abstract

Depression is a pervasive and debilitating neuropsychiatric disorder. A single, low dose of the NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant major depressive disorder. Developing mechanistic understanding of how NMDAR antagonism alters synapse and circuit function is pivotal to developing translatable, circuit-based therapies for depression. Here using viral vectors, anatomical tracing, fMRI, and optogenetic-assisted circuit analysis, we assessed the role of the NMDAR subunit GluN2B in regulating cellular, synaptic, and circuit-level function and depression-related behavior. We demonstrate that post-developmental deletion of GluN2B from pyramidal neurons in medial prefrontal cortex enhances action potential output in a synaptic activity-dependent manner. GluN2B deletion dictates functional connectivity between mPFC and limbic thalamus but not ventral hippocampus and elicits antidepressant-like behavior. Our findings demonstrate that postsynaptic GluN2B exerts inputspecific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

Advances in optogenetic studies of depressive-like behaviors and underlying neural circuit mechanisms

“…Another experiment confirmed that optogenetic activation of DA neurons in DRN could increase social preference as well ( 88 ). Projections originating from mPFC to different parts of thalamus are also demonstrated to regulate certain aspects of social behavior ( 89 – 91 ).…”