ABSTRACT
Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.
