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.
Highlights
Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line therapy for Major Depressive Disorder (MDD), and is commonly used for other neuropsychiatric disorders, including anxiety, obsessive compulsive, eating, and post-traumatic stress disorders [1]
The most significant reduction in Nrsn2 levels was observed following treatment with the Selective Serotonin Reuptake Inhibitors (SSRI) fluoxetine, which resulted in downregulation of Nrsn2 by 20.5 ± 6% (Fig. 1a)
We identified a novel, dynamic, and cell-type-specific signaling pathway, which is activated by chronic SSRIs in the dentate gyrus (DG) PV interneurons to regulate amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor (AMPAR) signaling and behavior
Summary
Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line therapy for Major Depressive Disorder (MDD), and is commonly used for other neuropsychiatric disorders, including anxiety, obsessive compulsive, eating, and post-traumatic stress disorders [1]. A typical delayed clinical response to SSRIs, ranging from 2 to 6 weeks [2], indicates that the mechanism of action of these agents requires slow adaptive changes, including neuronal plasticity. SSRIs-induced neuroplasticity was extensively documented in the limbic system, predominantly in the dentate gyrus (DG) of the hippocampus
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