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

Abstract

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.

• Authors: Corey Fee, Thomas D Prevot, Keith Misquitta, Daniel E Knutson, Guanguan Li, Prithu Mondal, James M Cook, Mounira Banasr, Etienne Sibille
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 24 Issue 6 Pg. 505-518 (07 14 2021) ISSN: 1469-5111 [Electronic] England
• PMID: 33438026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of CINP.

Chemical References

• GABA Agents
• Gabra5 protein, mouse
• Receptors, GABA-A
• Somatostatin

Topics

• Animals
• Behavior, Animal (drug effects)
• Behavioral Symptoms (drug therapy)
• Disease Models, Animal
• GABA Agents (pharmacology)
• GABAergic Neurons (drug effects)
• Genetic Techniques
• Genetic Vectors
• Interneurons (drug effects)
• Mice
• Mice, Inbred C57BL
• Receptors, GABA-A (drug effects)
• Somatostatin (metabolism)