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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Background: Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high levels of p11, a protein associated with depression and action of antidepressants. Methods: We characterized the behavioral response to subthreshold stress in mice with conditional deletion of p11 in PV cells. Using chemogenetics, viral-mediated gene delivery, and a specific ion channel agonist, we studied the role of dentate gyrus PV cells in regulating anxiety-like behavior and resilience to stress. We used electrophysiology, imaging, and biochemical studies in mice and cells to elucidate the function and mechanism of p11 in dentate gyrus PV cells. Results: p11 regulates the subcellular localization and cellular level of the potassium channel Kv3.1 in cells. Deletion of p11 from PV cells resulted in reduced hippocampal level of Kv3.1, attenuated capacity of high-frequency firing in dentate gyrus PV cells, and altered short-term plasticity at synapses on granule cells, as well as anxiety-like behavior and a pattern separation deficit. Chemogenetic inhibition or deletion of p11 in these cells induced vulnerability to depressive behavior, whereas upregulation of Kv3.1 in dentate gyrus PV cells or acute activation of Kv3.1 using a specific agonist induced resilience to depression. Conclusions: The activity of dentate gyrus PV cells plays a major role in the behavioral response to novelty and stress. Activation of the Kv3.1 channel in dentate gyrus PV cells may represent a target for the development of cell-type specific, fast-acting antidepressants.

Original languageAmerican English
Pages (from-to)405-414
Number of pages10
JournalBiological Psychiatry
Volume88
Issue number5
DOIs
StatePublished - 1 Sep 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Society of Biological Psychiatry

Keywords

  • Basket cells
  • Dentate gyrus
  • Kv3.1
  • Major depressive disorder
  • Parvalbumin
  • p11

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