Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Medrihan, Lucian; Umschweif, Gali; Sinha, Anjana; Reed, Shayna; Gindinova, Katherina; Sinha, Subhash C.; Greengard, Paul; Sagi, Yotam

doi:10.1101/784090

Cited by 6 publications

(8 citation statements)

References 46 publications

(60 reference statements)

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“…Taken together, these studies altogether suggest the PV inhibition as a common cellular mechanism associated with biological resilience as well as pharmacological actions of two different classes of antidepressants. Interestingly, a recent study by Medrihan et al suggested that decreased Kv3.1 channel and p11 function in PV vDG would confer susceptibility after stress (52). Although Ahnak cKO PV mice show resilience after CSDS (Figure 5F-J), p11 cKO PV mice show stress-susceptibility after SSDS(52), likely through many other binding partners of p11 in PV vDG including mGluR5, SMARCA3 and Supt6 (16,19).…”

Section: Discussionmentioning

confidence: 91%

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

Bhatti

Medrihan

Chen

et al. 2021

Preprint

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BACKGROUND: Behavioral responses to stress are, in part, mediated by the hippocampus and Parvalbumin (PV)-expressing neurons. However, whether chronic stress induces molecular and cellular adaptations in hippocampal PV neurons contribute to stress-induced behavioral outcomes remains elusive. METHOD: Using chronic social defeat stress (CSDS), we investigated the role of neuronal activity and gene expression in hippocampal PV neurons in mediating stress-resilience and -susceptibility. We first used in vivo high-density silicon probe recordings and chemogenetics to test whether the activity of PV neurons in ventral dentate gyrus (PVvDG) is associated with particular behavioral outcomes. To find critical molecular pathways associated with stress-resilience and -susceptibility, we used PV-neuron-selective translating ribosome affinity purification and RNAseq. We used immunoblotting, RNAscope, and region- or cell type-specific gene deletion to determine whether Ahnak, a molecule regulating depression-like behavior, was necessary for behavioral divergence after CSDS. RESULTS: We find CSDS modulates neuronal activity in vDG. Notably, stress-susceptibility is associated with an increase of PVvDG firing, which we find is necessary and sufficient for susceptibility. Additionally, genes involved in mitochondrial function, protein synthesis and synaptogenesis are differentially expressed in hippocampal PV neurons of stress-resilient and -susceptible mice. Interestingly, protein and mRNA levels of Ahnak, an endogenous regulator of L-type calcium channels are associated with susceptibility after CSDS. vDG- and PV cell type-specific deletions reveal that Ahnak is required for stress-susceptibility to CSDS. CONCLUSIONS: These findings indicate that CSDS-induced molecular and cellular adaptations in hippocampal PV neurons mediate behavioral consequences, proposing a mechanism underlying individual differences in stress vulnerability.

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Section: Discussionmentioning

confidence: 91%

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

Bhatti

Medrihan

Chen

et al. 2021

Preprint

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“…Such regulation includes different transcriptional programs controlling endocytosis [35]. In a recent study, we elucidated the involvement of p11, a SMARCA3-activity regulator protein, in modulating the endocytosis of potassium channel Kv3.1 in DG interneurons [36], suggesting that p11-SMARCA3 signaling mediates an endocytic program to regulate the activity of DG interneurons. Collectively, these findings support the idea that the p11-SMARCA3-Neurensin-2 signaling dynamically regulates a cellular endocytosis program in DG interneurons to mediate their function, AMPAR signaling, and consequently, to modulate emotional behavior.…”

Section: Neurensin-2 As a Potential Mediator Of Ampar Shuttling In Inmentioning

confidence: 98%

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

et al. 2021

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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.

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“…The behavioral response to chronic antidepressant treatment is mediated by p11 in DG cells, including cholecystokinin (CCK) [30] and parvalbumin (PV) [23] inhibitory interneurons, and the excitatory Mossy cells [31]. Among these, the two inhibitory interneurons also express Neurensin-2 , mirtazapine (mir), imipramine (imi), citalopram (cit) or fluoxetine (flx).…”

Section: P11-smarca3 Pathway In Parvalbumin-expressing Interneurons Mmentioning

confidence: 99%

“…We previously reported that chronic SSRIs and the subsequential induction in BDNF result in the upregulation of the antidepressant protein p11 [19,20]. p11 expression in the hippocampus is highly linked toresilience to stress and to the therapeutic effects of SSRIs [20][21][22][23]. Following chronic SSRIs, p11 binds SWI/ SNF-related, matrix-associated, actin-dependent regulator of chromatin 3 (SMARCA3) to mediate the behavioral response to the treatment [21,24].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Cited by 6 publications

References 46 publications

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

Molecular and cellular adaptations in hippocampal parvalbumin neurons mediate behavioral responses to chronic social stress

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

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

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