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

doi:10.1016/j.nbd.2024.106502

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

Neurobiol Dis. 2024 Jun 1:195:106502. doi: 10.1016/j.nbd.2024.106502. Epub 2024 Apr 10.

Authors

Affiliations

¹ 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.
² Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America.
³ Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, United States of America.
⁴ 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.
⁵ 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.
⁶ Neuroscience, Scripps College, Claremont, CA 91711, United States of America.
⁷ Department of Biology and Genetics, Stanford University, Stanford, CA 94305-5430, United States of America.
⁸ 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.
⁹ Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. Electronic address: wmobley@health.ucsd.edu.
¹⁰ Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. Electronic address: chw049@health.ucsd.edu.

PMID: 38608784
DOI: 10.1016/j.nbd.2024.106502

Abstract

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.

Keywords: BACHD; Brain-derived neurotrophic factor; Cortical neurons; Huntington's disease; Long term culture; Multi-array electrode; Neuronal activity; PSD95; Pre- and post-synaptic; Synapse; TRiC.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain-Derived Neurotrophic Factor* / metabolism
Cells, Cultured
Cerebral Cortex* / drug effects
Cerebral Cortex* / metabolism
Cerebral Cortex* / pathology
Disease Models, Animal*
Huntingtin Protein / genetics
Huntingtin Protein / metabolism
Huntington Disease* / metabolism
Huntington Disease* / pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons* / drug effects
Neurons* / metabolism
Neurons* / pathology
Synapses* / drug effects
Synapses* / metabolism
Synapses* / pathology
Synapsins / metabolism

Substances

Brain-Derived Neurotrophic Factor
Bdnf protein, mouse
Synapsins
Huntingtin Protein