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Mutant huntingtin expression in somatostatin-positive interneurons contributes to neurophysiological and behavioral phenotypes in BACHD mice.

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Τίτλος: Mutant huntingtin expression in somatostatin-positive interneurons contributes to neurophysiological and behavioral phenotypes in BACHD mice.
Συγγραφείς: Fowler JA; Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA.; Graduate Biomedical Sciences, Biochemistry and Structural Biology Theme, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA., Scarduzio M; Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA., Pool C; College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA 70125, USA.; Summer in Biomedical Sciences (SIBS) Undergraduate Research Program, The University of Alabama at Birmingham, Birmingham, AL 35294, USA., Mahan CD; Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA., Gray M; Department of Neurology, Killion Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA.
Πηγή: Disease models & mechanisms [Dis Model Mech] 2026 Mar 01; Vol. 19 (3). Date of Electronic Publication: 2026 Mar 27.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge : Company of Biologists Ltd., c2008-
Ιατρικοί όροι (MeSH): Interneurons*/metabolism , Huntingtin Protein*/metabolism , Huntingtin Protein*/genetics , Somatostatin*/metabolism , Mutation*/genetics , Mutant Proteins*/metabolism , Behavior, Animal*, Anxiety/physiopathology ; Anxiety/complications ; Huntington Disease/physiopathology ; Animals ; Phenotype ; Male ; Motor Activity ; Mice
Περίληψη: Huntington's disease (HD) is caused by expansion of the polyglutamine stretch in the widely expressed huntingtin (HTT) protein. Patients with HD have motor, psychiatric and cognitive changes due to changes in a variety of neural circuits. Somatostatin-expressing interneurons (SST-INs) can regulate neural circuits largely by inhibiting their target cells. Behaviorally, brain-wide inhibition of SST-INs increased anxiety in mice. Silencing striatal SST-INs caused a decrease in movement in the open field. Mutant HTT (mHTT)-expressing mice exhibited abnormal motor, cognitive and psychiatric-like changes, as well as electrophysiological changes in a variety of neurons, including striatal SST-INs. However, it is unknown whether cell-autonomous expression of mHTT in SST-INs contributes to HD-associated behavioral phenotypes or causes abnormal electrophysiological changes in striatal SST-INs. To address these questions, we reduced mHTT expression in SST-INs throughout the brain of BACHD mice. Our findings show that brain-wide reduction of mHTT in SST-INs rescues anxiety-like behavior in male BACHD mice in the light-dark box, without improving performance in the open field or on the rotarod. Additionally, expression of mHTT in striatal SST-INs cell autonomously drives their increased excitability.
(© 2026. Published by The Company of Biologists.)
Competing Interests: Competing interests The authors declare no competing or financial interests.
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Grant Information: 5R01NS089750 United States NS NINDS NIH HHS; Jarman F. Lowder Endowment; Hereditary Disease Foundation; University of Alabama at Birmingham
Contributed Indexing: Keywords: BACHD; Huntington's disease; Interneurons; Somatostatin; Striatum
Substance Nomenclature: 0 (Huntingtin Protein)
51110-01-1 (Somatostatin)
0 (Mutant Proteins)
Entry Date(s): Date Created: 20260206 Date Completed: 20260707 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13054931
DOI: 10.1242/dmm.052513
PMID: 41648922
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1754-8411
DOI:10.1242/dmm.052513