Developmental alterations of indirect-pathway medium spiny neurons in mouse models of Huntington’s disease

Lebouc M(1), Bonamy L(1), Dhellemmes T(1), Scharnholz J(1), Richard Q(1), Courtand G(2), Brochard A(3), Martins F(3), Landry M(1), Baufreton J(4), Garret M(2).

Author information:
(1)Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
(2)Univ. Bordeaux, CNRS, INCIA, UMR 5297, F-33000 Bordeaux, France.
(3)Univ. Bordeaux, INSERM, Neurocentre Magendie, U1215, F-33000 Bordeaux, France.
(4)Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France. Electronic address: .

Huntington’s disease (HD) is a complex neurodegenerative disorder with cognitive
and motor symptoms that typically manifest in adulthood. However, embryonic
brain development impairments leading to cortical defects in HD mutation
carriers has been shown recently supporting a neurodevelopmental component in
HD. Despite HD is primarily recognized as a striatal pathology, developmental
alterations in this structure, particularly during the early postnatal period,
remain poorly understood. To fill this gap, we examined striatal development in
newborn R6/1 mice. We found that D2 receptor-expressing indirect-pathway medium
spiny neurons (D2-MSNs) present in the matrix striatal compartment undergo early
morphological and electrophysiological maturation. Altered electrophysiological
properties were also observed in newborn CAG140 mice. Additionally, we also
observed a D2-MSN-selective reduction in glutamatergic cortico-striatal
transmission at the beginning of the second postnatal week as well as a reduced
projection of D2-MSNs onto the GPe at birth in R6/1 mice. All these alterations
were transient with the circuit normalizing after the second postnatal week.
These results identify a compartment- and cell-type specific defect in D2-MSNs
maturation, which can contribute in their latter vulnerability, as this
cell-type is the first to degenerate in HD during adulthood.

Copyright © 2025. Published by Elsevier Inc.

Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.

Auteurs Bordeaux Neurocampus