Identification of Neurensin-2 as a novel modulator of emotional behavior

Gali Umschweif, Lucian Medrihan, Andrés Guillén-Samander, Wei Wang, Yotam Sagi*, Paul Greengard

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 languageAmerican English
Pages (from-to)2872-2885
Number of pages14
JournalMolecular Psychiatry
Issue number7
StatePublished - Jul 2021
Externally publishedYes

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