Abnormal neurodevelopment predisposes to cortical hyperexcitability in Huntington's disease

Abstract

Accumulating morphological and electrophysiological evidence demonstrates that abnormal brain development is a key element in the progression of Huntington's disease (HD). Mutant huntingtin affects corticogenesis, cell migration, and differentiation. Cortical changes are reminiscent of focal cortical dysplasia, a malformation of cortical development that leads to hyperexcitability and epilepsy. Striatal development also is affected by the mutation. In animal models, recent studies provide additional evidence that neuronal morphology and intrinsic and electrophysiological properties deviate from normal development. Some changes indicate delayed development of cortical pyramidal neurons, while a subtype of striatal projection neuron displays a transient accelerated maturation. However, the brain is able to compensate for early abnormalities and, during a variable latent period, brain function appears normal. Eventually, homeostatic mechanisms begin to fail, resulting in the emergence of HD symptoms. The realization that neurodevelopment in HD is abnormal offers new insights and opens new avenues for early treatment. In this review, we present a brief summary of imaging and morphological studies from human carriers of the HD mutation followed by a more in-depth examination of recent findings in genetic animal models.

Plain Language Summary Abstract

Although Huntington's disease (HD) is considered primarily a neurodegenerative disorder, recent data has demonstrated that brain development is altered. Indeed, anatomical and functional changes occur very early in development and may set the stage for cell loss later in life. This article reviews recent evidence from clinical and basic research studies demonstrating that abnormal brain development increases the intrinsic excitability of brain cells. Although the brain tries to cope against increased excitability, compensatory mechanisms eventually fail. Early intervention is paramount to prevent brain deterioration and HD symptoms.