Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits

Kuldeep Tripathi, Yunus Emre Demiray, Stefanie Kliche, Liang Jing, Somoday Hazra, Joyeeta Dutta Hazra, Gal Richter-Levin, Oliver Stork

Research output: Contribution to journalArticlepeer-review

Abstract

A high degree of regional, temporal and molecular specificity is evident in the regulation of GABAergic signaling in stress-responsive circuitry, hampering the use of systemic GABAergic modulators for the treatment of stress-related psychopathology. Here we investigated the effectiveness of local intervention with the GABA synthetic enzymes GAD65 and GAD67 in the dorsal dentate gyrus (dDG) vs ventral DG (vDG) to alleviate anxiety-like behavior and stress-induced symptoms in the rat. We induced shRNA-mediated knock down of either GAD65 or GAD67 with lentiviral vectors microinjected into the dDG or vDG of young adult male rats and examined anxiety behavior, learning and memory performance. Subsequently we tested whether reducing GAD65 expression in the dDG would also confer resilience against juvenile stress-induced behavioral and physiological symptoms in adulthood. While knock down of either isoform in the vDG increased anxiety levels in the open field and the elevated plus maze tests, the knock down of GAD65, but not GAD67, in the dDG conferred a significant reduction in anxiety levels. Strikingly, this manipulation also attenuated juvenile stress evoked anxiety behavior, cognitive and synaptic plasticity impairments. Local GABAergic circuitry in the DG plays an important and highly region-specific role in control of emotional behavior and stress responding. Reduction of GAD65 expression in the dDG appears to provide resilience to juvenile stress-induced emotional and cognitive deficits, opening a new direction towards addressing a significant risk factor for developing stress and trauma-related psychopathologies later in life.

Original languageEnglish
Article number100350
JournalNeurobiology of Stress
Volume15
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
We are grateful to S. Stork, R. Anunu for expert technical assistance and to S. Mandel for editing the manuscript. This work was supported by funds of the German Research Foundation ( STO488/6 to OS and GRL, CRC779 TPB5 to OS) and by The Israeli Science Foundation (grant no. 1517/16 ), and by the State of Israel Ministry of Science & Technology award (Grant no. 3-14356 ).

Publisher Copyright:
© 2021

Keywords

  • Dentate gyrus
  • GABA
  • GAD65
  • GAD67
  • PTSD
  • Stress resilience

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

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