Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation
| العنوان: | Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation |
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| المؤلفون: | Corey Fee, Daniel E. Knutson, Keith A. Misquitta, James M. Cook, Guanguan Li, Mounira Banasr, Etienne Sibille, Prithu Mondal, Thomas D. Prevot |
| المصدر: | International Journal of Neuropsychopharmacology |
| بيانات النشر: | Oxford University Press, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | endocrine system, AcademicSubjects/MED00415, Gabra5, GABA Agents, GABRA5, Genetic Vectors, Behavioral Symptoms, Regular Research Articles, gamma-Aminobutyric acid, 03 medical and health sciences, GABA, Mice, 0302 clinical medicine, Interneurons, parasitic diseases, medicine, Animals, Pharmacology (medical), GABAergic Neurons, Receptor, 030304 developmental biology, Pharmacology, 0303 health sciences, antidepressant, biology, Behavior, Animal, GABAA receptor, AcademicSubjects/SCI01870, fungi, Long-term potentiation, medicine.disease, Receptors, GABA-A, Mice, Inbred C57BL, Psychiatry and Mental health, Disease Models, Animal, medicine.anatomical_structure, Mood disorders, Genetic Techniques, depression, biology.protein, Antidepressant, Neuron, Somatostatin, Neuroscience, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, medicine.drug |
| الوصف: | Introduction Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions; that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”); and that disinhibiting SST+ cells has antidepressant-like effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy. Methods We developed a mouse model allowing chemogenetic manipulation of brain-wide SST+ cells and employed behavioral characterization 30 minutes after repeated acute silencing to identify contributions to symptom-related behaviors. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits. Results Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant- and anxiolytic-like improvements among behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion Our data validate SST+ cells as regulators of mood and cognitive functions and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted therapeutic strategy. |
| اللغة: | English |
| تدمد: | 1469-5111 1461-1457 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7b39e914e4e66b48e6c06e8ec35da05fTest http://europepmc.org/articles/PMC8278801Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7b39e914e4e66b48e6c06e8ec35da05f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14695111 14611457 |
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