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Cell Rep. 2017 Aug 22;20(8):1867-1880. doi: 10.1016/j.celrep.2017.08.002.

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.

Author information

1
Roche Innovation Center Basel, Basel 4070, Switzerland; Tulane Brain Institute, Tulane University, New Orleans, LA 70115, USA.
2
Roche Innovation Center Basel, Basel 4070, Switzerland.
3
Faculté de Médecine, Université de Strasbourg, Strasbourg 67000, France.
4
Roche Innovation Center Basel, Basel 4070, Switzerland; Tulane Brain Institute, Tulane University, New Orleans, LA 70115, USA. Electronic address: benjamin.hall@roche.com.

Abstract

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.

KEYWORDS:

GluN2B; NMDAR; chemogenetics; depression; ketamine; medial dorsal thalamus; motivation; optogenetics; thalamocortical

PMID:
28834750
DOI:
10.1016/j.celrep.2017.08.002
[Indexed for MEDLINE]
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