TESTING CHOLESTEROL REPLENISHMENT IN PRODROMAL HUNTINGTON’S DISEASE: EFFECTS ON CIRCUIT-SPECIFIC SYNAPTIC RESPONSES AND PLASTICITY

Huntington’s disease (HD) is an autosomal dominant neurological disease, characterized by the degeneration of striatal neurons and cortico-striatal projections. Brain cholesterol synthesis and trafficking are altered in HD, contributing to neuronal dysfunction.
We characterized early cortico-striatal synaptopathy in a mouse model of prodromal HD, which presented with cognitive decline but no overt motor manifestations. In this setting, we tested whether central cholesterol delivery could prevent the onset of cortico-striatal synaptic dysfunction.
After systemic chronic treatment with brain-permeable nanoparticles loaded with cholesterol, 20-week-old zQ175DN knock-in mice were tested through ex vivo patch-clamp recordings and optogenetic stimulation to assess circuit-specific excitatory neurotransmission and synaptic plasticity. Immunofluorescence, electron microscopy, and molecular analysis of striatal synaptosomes were used for structural characterization.
In prodromal HD mice, we found reduced density of cortico-striatal projections and impaired excitatory tone. Long-term synaptic plasticity is lost in both striatal medium spiny neurons and cholinergic interneurons. We further investigated this phenomenon by pharmacologically isolating AMPAR- and NMDAR-mediated postsynaptic currents. Biochemical characterization of striatal synaptosomes highlighted a possible molecular link between cholesterol dysfunction and early synaptopathy. The effects of preemptive cholesterol administration on excitatory neurotransmission and long-term plasticity were tested, and electrophysiological outcomes were further validated by testing putative cholesterol-binding proteins in striatal synaptosomes.
Our work demonstrated that cortico-striatal disconnection can be assessed as early as in premotor HD, and that it is sustained by both presynaptic and postsynaptic phenomena. Cholesterol dyshomeostasis plays a role in cortico-striatal synaptopathy and may represent a potential target for halting network dysfunction in HD.