Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation

Fee, Corey1,2,3; Prevot, Thomas D.1,2,3; Misquitta, Keith1,2,3; Knutson, Daniel E.4,5; Li, Guanguan4,5; Mondal, Prithu4,5; Cook, James M.4,5; Banasr, Mounira1,2,3; Sibille, Etienne1,2,3

2021-06-01

10.1093/ijnp/pyab002

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY   影响因子和分区

1461-1457

1469-5111

["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, alpha 5-GABAA receptor positive allosteric modulators (alpha 5-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 alpha 5-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 alpha 5-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 alpha 5-PAM represents a targeted therapeutic strategy."]

Somatostatin GABA depression Gabra5 antidepressant

SCI

英语

其他

Brain and Behavior Research Foundation[24034,25637] ; Canadian Institutes of Health Research["PJT-165852","PJT-153175"]

Neurosciences & Neurology ; Pharmacology & Pharmacy ; Psychiatry

Clinical Neurology ; Neurosciences ; Pharmacology & Pharmacy ; Psychiatry

WOS:000684144300007

OXFORD UNIV PRESS

PSYCHIATRY/PSYCHOLOGY

Web of Science

1.Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON, Canada
2.Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada
3.Univ Toronto, Dept Psychiat, Toronto, ON, Canada
4.Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53201 USA
5.Southern Univ Sci & Technol, Coll Sci, Dept Chem, Shenzhen Key Lab Small Mol Drug Discovery & Synth, Shenzhen, Peoples R China

Fee, Corey,Prevot, Thomas D.,Misquitta, Keith,et al. Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation[J]. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY,2021,24(6).

Fee, Corey.,Prevot, Thomas D..,Misquitta, Keith.,Knutson, Daniel E..,Li, Guanguan.,...&Sibille, Etienne.(2021).Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation.INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY,24(6).

Fee, Corey,et al."Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation".INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 24.6(2021).