Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior

The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior. [Display omitted] •Deleting GluN2B from pyramidal neurons of the mPFC causes antidepressant-like behavior•GluN2B-containing NMDARs regulate synaptic input to mPFC from the medial dorsal thalamus•GluN2B deletion has negligible effect on mPFC synaptic inputs from the ventral hippocampus•Activating medial dorsal thalamus inputs to the mPFC causes antidepressant-like behavior In these experiments, Miller et al. show that GluN2B-containing NMDARs are enriched at synapses between the medial dorsal thalamus and medial prefrontal cortex. They also show that post-developmental deletion of these receptors in the mPFC enhances synaptic connectivity and that direct activation of this circuit in vivo drives strong antidepressant-like behavior in mice.