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Authors & Affiliations
Francesco Mainardi, Eleonora Pali, Giuseppe Sciamanna, Francesca Prestori, Lisa Mapelli, Antonio Pisani, Egidio D'Angelo
Abstract
DYT1 is an autosomal dominant form of dystonia, linked to a deletion (ΔGAG) in the TOR1A gene. The basal ganglia have been found to play a crucial role in the development of dystonia in the TOR1AΔGAG murine model. Experimental evidence has also indicated that the cerebellar cortex is likely to play a pivotal role in the pathophysiology of this disorder. We investigated cerebellar cortex activity and synaptic plasticity by performing extracellular recordings in acute parasagittal cerebellar slices with a high-density multielectrode array (HD-MEA) that allows to simultaneously record the activity of several neurons distributed in the whole network. We acquired spontaneous activity and stimulus-induced responses to mossy fiber stimulation, such as local field potentials (LFP) in the granular layer. The network activity was also characterized after the induction of long-term synaptic plasticity at the mossy fibers-granule cell relay in both WT and TOR1AΔGAG, using a high-frequency stimulation at 100Hz for 1 second.A separate set of experiments was performed using whole-cell patch-clamp recordings to investigate the passive membrane properties and intrinsic excitability of cerebellar granule cells and Purkinje cells in WT and TOR1AΔGAG. We also characterized excitatory postsynaptic currents in granule cells following mossy fiber stimulation, to address the short-term synaptic dynamics at the cerebellum input stage.These data will be crucial to understand the role of different neuronal types in shaping the cerebellar cortex activity in the DYT1 mouse model compared to the WT, helping to uncover differences in signal integration and processing in this pathological model.