Research Group: Toselli Mauro, Biella Gerardo

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, neuropsychiatric, and cognitive deficits. HD is caused by an expansion of a CAG triplet repeat stretch in huntingtin gene. The resulting mutant Huntingtin protein is toxic to neuronal cells and causes the death of cortical pyramidal neurons (CPNs) and striatal medium-size spiny neurons (MSNs). Classically, neuronal death has been thought to underlie most of the symptoms of HD. However, growing evidences suggest that progressive alterations in morphology and functionality of CPNs and MSNs could precede neuronal death and underpin the disease. In particular severe corticostriatal connectivity and plasticity impairments and NMDA receptors-mediated excitotoxicity have been reported in HD. These evidences support the hypothesis that HD is primarily a synaptopathy that selectively impairs the corticostriatal projections. However, very little research has been done to understand what early synaptic dysfunctions develop that ultimately lead to the disease. This project will analyze the impairment of the excitatory corticostriatal synaptic pathway in a knock-in mouse model of HD (heterozygous zQ175 mice), in both the symptomatic (early and late) and the less explored pre-symptomatic stages of the disease. The main goal will be to identify the alterations of the biophysical properties of the MSNs as well as the connectivity and plasticity impairments at the corticostriatal synapses before the onset of HD, at the onset of the clinical symptoms, and during HD progression, by performing electrophysiological experiments on brain slices. A particular focus will be put on identifying functional alterations in NMDA receptors.

Recent Publications:

• Delli Carri A, Onorati M, Lelos MJ, Castiglioni V, Faedo A, Menon R, Camnasio S, Vuono R, Spaiardi P, Talpo F, Toselli M, Martino G, Barker RA, Dunnett SB, Biella G, Cattaneo E. (2013) Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development. 140: 301-312. doi: 10.1242/dev.084608. PMID: 23250204.
• Delli Carri A, Onorati M, Castiglioni V, Faedo A, Camnasio S, Toselli M, Biella G, Cattaneo E. (2013) Human pluripotent stem cell differentiation into authentic striatal projection neurons. Stem Cell Rev. 9: 461-474. doi: 10.1007/s12015-013-9441-8. PMID: 23625190.
• Onorati M., Castiglioni V., Biasci D., Cesana E., Menon R., Vuono R., Talpo F., Goya R.L., Lyons P.A., Bulfamante G.P., Muzio L., Martino G., Toselli M., Farina C., Barker R.A., Biella G., Cattaneo E.. (2014) Molecular and functional definition of the developing human striatum. Nat Neurosci. 17:1804-1815. doi: 10.1038/nn.3860. PMID: 25383901.