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bioRxiv · 10.1101/106419

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

Miller, O. H.·Bruns, A.·Ben Ammar, I.·Mueggler, T.·Hall, B. J.
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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 input-specific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

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Miller, O. H., Bruns, A., Ben Ammar, I., Mueggler, T., Hall, B. J.. 2017-04-07. Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation. https://doi.org/10.1101/106419

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