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HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic
Marina Kovalenko1,2, Austen Milnerwood3, James Giordano1,2
1Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Journal of Huntington'S Disease
|February 27, 2018
Summary
Huntington's disease (HD) mouse models show early brain changes and neuronal dysfunction, even without neurodegeneration. These findings highlight the need for early therapeutic intervention in HD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) requires early intervention for effective disease-modifying therapy.
- Identifying phenotypes proximal to the HTT CAG repeat expansion is crucial for early therapeutic targeting.
Purpose of the Study:
- To utilize Htt CAG knock-in mice, precise genetic models of the human HTT mutation, for studying early Huntington's disease events.
- To investigate the pathological and functional consequences of the HTT CAG repeat expansion in a mouse model.
Main Methods:
- Analysis of B6J.HttQ111/+ mice across a lifespan (2-18 months).
- Assessment of pathological markers including immunohistochemistry, brain volumes, cortical thickness, CAG instability, and striatal synapse ultrastructure.
- Electrophysiological recordings of glutamatergic transmission in striatal slices and evaluation of diet perturbation effects.
Main Results:
- HttQ111/+ mice exhibited region-specific brain volume and cortical thickness changes, decreased striatal DARPP-32, and altered synaptic structure without significant neurodegeneration or gliosis.
- Electrophysiology revealed abnormalities in AMPA and NMDA receptor-mediated currents, including elevated extrasynaptic NMDA currents.
- Dietary changes affected cortical thickness but not CAG expansion or other measured pathological markers.
Conclusions:
- A single HttQ111 allele is sufficient to induce early, brain region-specific morphological changes and neuronal dysfunction in Huntington's disease models.
- These findings indicate an insidious disease process beginning early in life, underscoring the importance of early intervention strategies for HD.