TY - JOUR
T1 - Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants
AU - Umschweif, Gali
AU - Medrihan, Lucian
AU - McCabe, Kathryn A.
AU - Sagi, Yotam
AU - Greengard, Paul
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85102776808&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01059-4
DO - 10.1038/s41380-021-01059-4
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C2 - 33723417
AN - SCOPUS:85102776808
SN - 1359-4184
VL - 26
SP - 3350
EP - 3362
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 7
ER -