Huntington’s Disease (HD) is a fatal neurodegenerative genetic disorder characterized by motor impairments, cognitive decline and psychiatric symptoms. Mutation of the huntingtin gene inducing a CAG triplet expansion with more than 36 repeats leads to a pathological phenotype, which in most cases exacerbates when the patient is in his/her 40s. Within the brain, the striatal Medium Spiny Neurons (MSNs) progressively degenerate. Among other pathological features, MSN intracellular calcium ion levels are increased. It was recently shown that the beta-4 subunit of the voltage-gated sodium channel (Nav) (encoded by the SCN4B gene) is down-regulated in the striatum of both human post-mortem tissue and rodent models of HD (Oyama et al., 2006 ; Miyazaki et al., 2014). Here, we aim to investigate the role of beta-4 in MSN excitability, in their degeneration and thus in the pathophysiology of HD. HEK cells expressing either hNav1.3, hNav1.6 or rNav1.2 isoform were co-transfected with beta-4, to assess the impact of its presence or absence on sodium channel gating. Beta-4 induces a hyperpolarized shift in the voltage-dependance of activation of both hNav1.3 (-21,04 ± 1,84mV sham vs -27,27 ± 1,77mV with beta-4, p<0.05) and hNav1.6 (-26,73±1,82mV sham vs -30,26 ± 0,75mV with beta-4, p<0.05). Increased intracellular calcium ion concentration shifted steady-state fast inactivation of Nav1.3 to more hyperpolarized potentials (-63,16 ± 1,19mV without Ca2+ vs -71,51 ± 2,13mV with Ca2+, p<0.05). To investigate HD-related changes in a more physiological system, we differentiated human induced-pluripotent stem cells (iPSCs) into MSN-like cells according to a published protocol (Stanslowsky et al., 2016). Following 55±3 maturation days, neurons from one HD carrying 72 CAG repeats and two control iPSC lines were recorded using patch clamp, with and without an elevated intracellular calcium ion concentration, to study the electrical activity of Navs in these cells. Preliminary results suggest that Nav activity does not seem to be affected by the HD mutation at this time point. While heterologous expression shows effects of beta-4 expression on sodium channel gating, the iPSC derived MSN-like cells of HD patients may not be old enough yet to show a phenotype. Further adaptation of the differentiation protocol is therefore needed. On the meeting, an immunocytochemical characterization of the MSNs, their sodium channel electrophysiological properties in both voltage-clamp and current-clamp and marker expression will be presented.