Striatal Neuron Excitability Is Regulated by Huntingtin in the Adult Brain

Huntington's disease (HD) is a hereditary neurodegenerative disease that typically presents during midlife and is characterized by a combination of motor, cognitive, and psychiatric symptoms. HD is fatal and arises from a mutation in the huntingtin (HTT) gene, which results in decreased neuronal health followed by brain atrophy, with spiny projection neurons (SPNs) of the striatum being especially vulnerable to degeneration. HTT loss of function, caused by haploinsufficiency of the wild-type HTT gene (wtHTT), is an important feature of HD pathophysiology that has previously been understudied compared with mutant HTT gain-of-function mechanisms. wtHTT is essential for nervous system development and functions as a scaffolding protein to support many vital cellular functions including axonal transport, autophagy, and synaptic plasticity. Here, we examined the consequences of wtHTT deletion in the adult cortex and striatum by conditionally inactivating wtHTT in 2-4-month-old male and female Htt ^fl/fl mice. wtHTT loss of function decreased intrinsic neuronal excitability within SPNs and produced a neuroinflammatory response in these mice, while tissue organization, spine morphology, and motor behavior remained unaffected. Results presented here provide additional evidence that wtHTT is vital for maintaining neuronal health in the adult brain and highlight some potential adverse consequences of nonselective HTT lowering for the treatment of HD.