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 documented in human and animal HD models.
• 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 pyramidal neurons and striatal medium spiny neurons.

Main Methods:

• Examined wildtype (WT) and R6/2 mice at postnatal days 7, 14, and 21.
• Utilized morphological examination and ex vivo electrophysiological recordings.
• Assessed intrinsic membrane properties and synaptic activity of cortical pyramidal neurons and striatal medium spiny neurons.

Main Results:

• R6/2 cortical pyramidal neurons exhibited early alterations including reduced capacitance, increased resistance, and delayed maturation.
• Striatal medium spiny neurons showed transient deficits in GABAergic inputs that normalized by P21.
• Cortical alterations preceded striatal changes, with some R6/2 neuronal properties normalizing by P21.

Conclusions:

• The developing Huntington's disease brain demonstrates compensatory mechanisms for early developmental abnormalities.
• Cortical maldevelopment appears to precede and contribute to subsequent striatal alterations.
• Targeting cortical maldevelopment may offer a strategy to prevent or delay Huntington's disease progression.