Unraveling the crucial role of huntingtin in synaptic plasticity and neuronal health in the adult brain

Abstract

Huntington’s disease (HD) is a monogenic neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. Many promising therapeutics have entered clinical trials that treat HD by targeting its root cause: mutant HTT (mHTT). These drugs deplete mHTT at the ribonucleic acid (RNA) or protein level; however, many are non-selective and reduce both mHTT and wild-type HTT (wtHTT). Non-pathogenic wtHTT is essential for nervous system development and regulates myriad crucial cellular functions, including axonal transport, transcription and autophagy. As most HD research has focused on the gain-of-function effects of mHTT, the consequences of wtHTT-lowering are not fully understood. Elucidating the consequences of wtHTT loss in the adult brain is essential as HD patients entering clinical trials have 50% wtHTT protein levels that are further reduced by non-selective therapeutics. The aim of this dissertation is to investigate the consequences of wtHTT-lowering in the adult brain. The present thesis begins by reviewing the role of wtHTT in synaptic function, as HD is considered, like many other neurodegenerative diseases, to be a synaptopathy, and synaptic dysfunction both precedes and predicts the onset of HD. This thesis highlights a plethora of studies that suggest a role for wtHTT as a major regulator of synaptic function in the adult brain. From here, the consequences of wtHTT-lowering in vitro and in vivo are examined, mainly focusing on wtHTT depletion in hippocampal neurons, as HD models display severe hippocampal synaptic dysfunction. Results from this dissertation show that wtHTT-lowered primary neurons have altered nuclear morphology and a loss of transcriptional repression. In vivo, 1-2 month conditional deletion of wtHTT results in widespread changes in morphology, extensive neuroinflammation, synaptic plasticity failures in the adult mouse hippocampus, and spatial learning and memory deficits 6-8 months post-deletion. When compared to the HD-vulnerable striatum, 1-2 month wtHTT knockout in the mouse striatum was not found to impact morphology but did lead to neuroinflammation and reduced intrinsic excitability in a similar manner as what was seen in the hippocampus. This thesis emphasizes the importance of maintaining sufficient neuronal wtHTT levels in the adult brain, an essential consideration for the development of HTT-lowering therapeutics.