Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits
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 in...
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doaj-8a3ec1d824004448aa1f51d6cc42d94c2021-06-09T05:58:32ZengElsevierNeurobiology of Stress2352-28952021-11-0115100350Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficitsKuldeep Tripathi0Yunus Emre Demiray1Stefanie Kliche2Liang Jing3Somoday Hazra4Joyeeta Dutta Hazra5Gal Richter-Levin6Oliver Stork7Sagol Department of Neurobiology, University of Haifa, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Israel; Psychology Department, University of Haifa, IsraelDepartment of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University, Magdeburg, GermanyInstitute for Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, GermanySagol Department of Neurobiology, University of Haifa, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, IsraelSagol Department of Neurobiology, University of Haifa, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, IsraelSagol Department of Neurobiology, University of Haifa, IsraelSagol Department of Neurobiology, University of Haifa, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Israel; Psychology Department, University of Haifa, Israel; Corresponding author. Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University, Magdeburg, Germany; Center for Behavioral Brain Science, Magdeburg, Germany; Corresponding author. Center for Behavioral Brain Science, Magdeburg, GermanyA 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.http://www.sciencedirect.com/science/article/pii/S2352289521000588PTSDGABAGAD65GAD67Dentate gyrusStress resilience |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kuldeep Tripathi Yunus Emre Demiray Stefanie Kliche Liang Jing Somoday Hazra Joyeeta Dutta Hazra Gal Richter-Levin Oliver Stork |
spellingShingle |
Kuldeep Tripathi Yunus Emre Demiray Stefanie Kliche Liang Jing Somoday Hazra Joyeeta Dutta Hazra Gal Richter-Levin Oliver Stork Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits Neurobiology of Stress PTSD GABA GAD65 GAD67 Dentate gyrus Stress resilience |
author_facet |
Kuldeep Tripathi Yunus Emre Demiray Stefanie Kliche Liang Jing Somoday Hazra Joyeeta Dutta Hazra Gal Richter-Levin Oliver Stork |
author_sort |
Kuldeep Tripathi |
title |
Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
title_short |
Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
title_full |
Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
title_fullStr |
Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
title_full_unstemmed |
Reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
title_sort |
reducing glutamic acid decarboxylase in the dorsal dentate gyrus attenuates juvenile stress induced emotional and cognitive deficits |
publisher |
Elsevier |
series |
Neurobiology of Stress |
issn |
2352-2895 |
publishDate |
2021-11-01 |
description |
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. |
topic |
PTSD GABA GAD65 GAD67 Dentate gyrus Stress resilience |
url |
http://www.sciencedirect.com/science/article/pii/S2352289521000588 |
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