Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior
Summary: Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABAA subunit-containing GABAA receptors (δGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABAA (cerebellar [cb] δ knockout [KO]...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720313279 |
| _version_ | 1818456876037177344 |
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| author | Stephanie Rudolph Chong Guo Stan L. Pashkovski Tomas Osorno Winthrop F. Gillis Jeremy M. Krauss Hajnalka Nyitrai Isabella Flaquer Mahmoud El-Rifai Sandeep Robert Datta Wade G. Regehr |
| author_facet | Stephanie Rudolph Chong Guo Stan L. Pashkovski Tomas Osorno Winthrop F. Gillis Jeremy M. Krauss Hajnalka Nyitrai Isabella Flaquer Mahmoud El-Rifai Sandeep Robert Datta Wade G. Regehr |
| author_sort | Stephanie Rudolph |
| collection | DOAJ |
| description | Summary: Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABAA subunit-containing GABAA receptors (δGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABAA (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb δ KO mice display deficits in many behaviors, but motor function is normal. Strikingly, δGABAA deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that δGABAARs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias. |
| first_indexed | 2024-12-14T22:33:38Z |
| format | Article |
| id | doaj.art-682044dfb8cb4261a2b5d5bdd530af5e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T22:33:38Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-682044dfb8cb4261a2b5d5bdd530af5e2022-12-21T22:45:12ZengElsevierCell Reports2211-12472020-11-01335108338Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of BehaviorStephanie Rudolph0Chong Guo1Stan L. Pashkovski2Tomas Osorno3Winthrop F. Gillis4Jeremy M. Krauss5Hajnalka Nyitrai6Isabella Flaquer7Mahmoud El-Rifai8Sandeep Robert Datta9Wade G. Regehr10Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Corresponding authorSummary: Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABAA subunit-containing GABAA receptors (δGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABAA (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb δ KO mice display deficits in many behaviors, but motor function is normal. Strikingly, δGABAA deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that δGABAARs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias.http://www.sciencedirect.com/science/article/pii/S2211124720313279cerebellumtonic inhibitionGABAAhyperexcitabilityanxiety-like behaviorsocial behavior |
| spellingShingle | Stephanie Rudolph Chong Guo Stan L. Pashkovski Tomas Osorno Winthrop F. Gillis Jeremy M. Krauss Hajnalka Nyitrai Isabella Flaquer Mahmoud El-Rifai Sandeep Robert Datta Wade G. Regehr Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior Cell Reports cerebellum tonic inhibition GABAA hyperexcitability anxiety-like behavior social behavior |
| title | Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior |
| title_full | Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior |
| title_fullStr | Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior |
| title_full_unstemmed | Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior |
| title_short | Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior |
| title_sort | cerebellum specific deletion of the gabaa receptor δ subunit leads to sex specific disruption of behavior |
| topic | cerebellum tonic inhibition GABAA hyperexcitability anxiety-like behavior social behavior |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720313279 |
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