Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants

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Abstract

The delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.

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Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

Ronald S. Duman, George Aghajanian, Gerard Sanacora … (2016)

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

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NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Panos Zanos, Ruin Moaddel, Patrick Morris … (2016)

Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants.

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mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.

Nanxin Li, Boyoung Lee, Rong-Jian Liu … (2010)

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

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Author and article information

Contributors

Yotam Sagi:

ORCID: http://orcid.org/0000-0002-7413-0698

ysagi@rockefeller.edu

Journal

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol Psychiatry

Title: Molecular Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date (Electronic): 15 March 2021

Publication date PMC-release: 15 March 2021

Publication date (Print): 2021

Volume: 26

Issue: 7

Pages: 3350-3362

Affiliations

GRID grid.134907.8, ISNI 0000 0001 2166 1519, Laboratory of Molecular and Cellular Neuroscience, , The Rockefeller University, ; New York, NY USA

Author information

Yotam Sagi http://orcid.org/0000-0002-7413-0698

Article

Publisher ID: 1059

DOI: 10.1038/s41380-021-01059-4

PMC ID: 8505248

PubMed ID: 33723417

SO-VID: b7191d35-60cc-43c7-b717-c2676221a4a0

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 June 2020

Date revision received : 2 February 2021

Date accepted : 18 February 2021

Funding

Funded by: United States Army Medical Research Acquisition Activity Grant W81XWH-14-0390. The National Center for Advancing Translational Sciences, National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program grant UL1TR001866.

Funded by: FundRef https://doi.org/10.13039/100007457, JPB Foundation;

Funded by: FundRef https://doi.org/10.13039/100001621, Fisher Center for Alzheimer’s Research Foundation (Fisher Center Foundation);

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ScienceOpen disciplines: Molecular medicine

Keywords: neuroscience,depression

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ScienceOpen disciplines: Molecular medicine

Keywords: neuroscience, depression

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Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants

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Most cited references 51

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.

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