Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation.
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
GABA
Gabra5
Somatostatin
antidepressant
depression
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
14 07 2021
14 07 2021
Historique:
received:
18
08
2020
revised:
15
12
2020
accepted:
11
01
2021
pubmed:
14
1
2021
medline:
1
2
2022
entrez:
13
1
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33438026
pii: 6092647
doi: 10.1093/ijnp/pyab002
pmc: PMC8278801
doi:
Substances chimiques
GABA Agents
0
Gabra5 protein, mouse
0
Receptors, GABA-A
0
Somatostatin
51110-01-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
505-518Subventions
Organisme : CIHR
ID : PJT-165852
Pays : Canada
Organisme : CIHR
ID : PJT-153175
Pays : Canada
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.
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