Abstract
Among the hallmarks of major depressive disorders (MDD) are molecular, functional, and morphological impairments in the hippocampus. Recent studies suggested a key role for hippocampal GABAergic interneurons both in depression and in the response to its treatments. These interneurons highly express the chromatin-remodeler SMARCA3 which mediates the response to chronic antidepressants in an unknown mechanism. Using cell-type-specific molecular and physiological approaches, we report that SMARCA3 mediates the glutamatergic signaling in interneurons by repressing the expression of the neuronal protein, Neurensin-2. This vesicular protein associates with endosomes and postsynaptic proteins and is highly and selectively expressed in subpopulations of GABAergic interneurons. Upregulation of Neurensin-2 in the hippocampus either by stress, viral overexpression, or by SMARCA3 deletion, results in depressive-like behaviors. In contrast, the deletion of Neurensin-2 confers resilience to stress and induces AMPA receptor localization to synapses. This pathway which bidirectionally affects emotional behavior could be involved in neuropsychiatric disorders, and suggests novel therapeutic approaches.
| Original language | American English |
|---|---|
| Pages (from-to) | 2872-2885 |
| Number of pages | 14 |
| Journal | Molecular Psychiatry |
| Volume | 26 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2021 |
| Externally published | Yes |
Bibliographical note
Funding Information:Acknowledgements We are grateful to Dr. Pietro De Camilli for his valuable discussion. To Dr. Henrik Molina from The Proteomics Resource Center, to Dr. Thomas Carroll from the Bioinformatics Resource Center, to Dr. Kunihiro Uryu from the Microscopy Resource Center and to Dr. Dorjee T.N. Shola at the Gene Targeting Resource Center, all at The Rockefeller University, and to Ms. Debra Poulter for proofreading. This work was supported by the United States Army Medical Research Acquisition Activity Grant W81XWH-14-0390 (YS), The JPB foundation (PG), The Fisher Center for Alzheimer’s Research Foundation (PG), The Leon Black Family Foundation (PG), NIH grant NS036251 (AG), The Shapiro-Silverberg Fund for the Advancement of Translational Research (YS) by funding from the Leona M. and Harry B. Helmsley Charitable Trust for funding for mass spectrometry.
Publisher Copyright:
© 2021, The Author(s).
