Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC...

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT).
• Clinical symptoms of HD typically appear in adulthood, despite mutant HTT expression from embryonic development.
• The reversibility of early, neurodevelopmental changes in HD remains largely unknown.

Purpose of the Study:

• To identify and characterize early behavioral, molecular, and cellular changes in preweaning Huntington disease (HD) rodent models.
• To investigate the potential of interventional therapy to reverse these early HD-associated alterations.

Main Methods:

• Utilized transgenic HD rats and mice to assess preweaning behavioral phenotypes (ultrasonic vocalization, prepulse inhibition, risk-taking).
• Examined dopaminergic regulation in vivo and neural stem/progenitor cell differentiation capacity in vitro and in vivo.
• Administered the histone deacetylase inhibitor (HDACi) LBH589 to assess therapeutic effects on identified early changes.

Main Results:

• Identified early behavioral deficits, dopaminergic dysregulation, and impaired neuronal/oligodendrocyte differentiation in preweaning HD models.
• LBH589 treatment significantly improved behavioral outcomes and dopaminergic markers.
• HDACi intervention led to complete reversal of aberrant neuronal differentiation in vitro and in vivo.

Conclusions:

• Neurodevelopmental alterations are present early in the course of Huntington disease (HD) and contribute to its prodromal phase.
• Early, presymptomatic intervention with histone deacetylase inhibitors (HDACi) shows promise for reversing neurodevelopmental deficits in HD.
• HDACi therapy represents a potential novel treatment strategy for Huntington disease.