BDNF and TRiC-inspired reagent rescue cortical synaptic deficits in a mouse model of Huntington's disease

Yingli Gu; Alexander Pope; Charlene Smith; Christopher Carmona; Aaron Johnstone; Linda Shi; Xuqiao Chen; Sarai Santos; Claire Cecile Bacon-Brenes; Thomas Shoff; Korbin M. Kleczko; Judith Frydman; Leslie M. Thompson; William C. Mobley; Chengbiao Wu

Neurobiology of Disease (Jun 2024)

BDNF and TRiC-inspired reagent rescue cortical synaptic deficits in a mouse model of Huntington's disease

Yingli Gu,
Alexander Pope,
Charlene Smith,
Christopher Carmona,
Aaron Johnstone,
Linda Shi,
Xuqiao Chen,
Sarai Santos,
Claire Cecile Bacon-Brenes,
Thomas Shoff,
Korbin M. Kleczko,
Judith Frydman,
Leslie M. Thompson,
William C. Mobley,
Chengbiao Wu

Affiliations

Yingli Gu: Department of Neurology, The Fourth Hospital of Harbin Medical University, 150001, China; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Alexander Pope: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Charlene Smith: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, United States of America
Christopher Carmona: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, United States of America; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, United States of America; Beckman Laser Institute & Medical Clinic, University of California, Irvine, Irvine, CA, United States; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, United States
Aaron Johnstone: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Linda Shi: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, United States of America; Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, United States of America; Beckman Laser Institute & Medical Clinic, University of California, Irvine, Irvine, CA, United States; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, United States
Xuqiao Chen: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Sarai Santos: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Claire Cecile Bacon-Brenes: Neuroscience, Scripps College, Claremont, CA 91711, United States of America
Thomas Shoff: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America
Korbin M. Kleczko: Department of Biology and Genetics, Stanford University, Stanford, CA 94305-5430, United States of America
Judith Frydman: Department of Biology and Genetics, Stanford University, Stanford, CA 94305-5430, United States of America
Leslie M. Thompson: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, United States of America; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, United States of America; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, United States of America; Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA 92697, United States of America
William C. Mobley: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America; Corresponding authors.
Chengbiao Wu: Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America; Corresponding authors.

Journal volume & issue: Vol. 195
p. 106502

Abstract

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Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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