Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.
Oliver H Miller, Andreas Bruns, Imen Ben Ammar, Thomas Mueggler, Benjamin J Hall
Cell Reports August 22, 2017 DOI: 10.1016/j.celrep.2017.08.002 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice |
| Topics | Depression Ketamine |
| Keywords | Glun2b Nmdar Chemogenetics Medial dorsal thalamus Motivation Optogenetics Thalamocortical |
| Key points | Post-developmental deletion of the NMDAR subunit GluN2B from medial prefrontal cortex pyramidal neurons in mice enhanced medial prefrontal cortex-limbic thalamus connectivity, but not ventral hippocampus connectivity, and reduced depression-like behavior. Chemogenetic activation of this thalamocortical circuit was sufficient to decrease despair-like behavior. The authors propose that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus-to-medial prefrontal cortex circuit controlling depression-like behavior. |
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.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 10
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
- The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors. Neuropharmacology November 1, 2018
- Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression. Molecular Psychiatry 2025
- Subanesthetic Ketamine Ameliorates Activity-Based Anorexia of Adult Mice. Synapse 2025
and 5 more in the library
Cites 4
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- Optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions Proceedings of the National Academy of Sciences June 8, 2015
- GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine Elife October 23, 2014
- Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure Biological Psychiatry February 3, 2011