Corticostriatal Maldevelopment in the R6/2 Mouse Model of Juvenile Huntington's Disease

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Huntington's disease (HD) is increasingly viewed as a neurodevelopmental disorder alongside its neurodegenerative aspects.
• Abnormalities in brain development are observed in human and animal models of HD.
• A concurrent study of cortical and striatal development in a genetic HD model was lacking.

Purpose of the Study:

• To investigate corticostriatal development in the R6/2 mouse model of juvenile Huntington's disease.
• To identify early structural and functional alterations in cortical and striatal neurons during development.

Main Methods:

• Examined wildtype (WT) and R6/2 mice at postnatal days 7, 14, and 21.
• Performed morphological examinations and ex vivo electrophysiological recordings of cortical pyramidal neurons (CPNs) and striatal medium-sized spiny neurons (MSNs).

Main Results:

• R6/2 CPNs showed early alterations including reduced membrane capacitance and increased input resistance, suggesting delayed cortical maturation.
• Striatal medium-sized spiny neurons (MSNs) exhibited delayed deficits in GABAergic inputs, normalizing by P21.
• Cortical alterations preceded and contributed to striatal changes, with some normalization observed by P21.

Conclusions:

• The developing brain in HD models can compensate for early developmental abnormalities.
• Cortical maldevelopment is a primary driver of striatal changes in juvenile HD.
• Targeting cortical maldevelopment may offer therapeutic strategies to prevent or delay HD progression.