title: GABAergic signaling and connectivity on Purkinje cells are impaired in experimental autoimmune encephalomyelitis.
abstract: A significant proportion of multiple sclerosis (MS) patients have functionally relevant cerebellar deficits, which significantly contribute to disability. Although clinical and experimental studies have been conducted to understand the pathophysiology of cerebellar dysfunction in MS, no electrophysiological and morphological studies have investigated potential alterations of synaptic connections of cerebellar Purkinje cells (PC). For this reason we analyzed cerebellar PC GABAergic connectivity in mice with MOG((35-55))-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We observed a strong reduction in the frequency of the spontaneous inhibitory post-synaptic currents (IPSCs) recorded from PCs during the symptomatic phase of the disease, and in presence of prominent microglia activation not only in the white matter (WM) but also in the molecular layer (ML). The massive GABAergic innervation on PCs from basket and stellate cells was reduced and associated to a decrease of the number of these inhibitory interneurons. On the contrary no significant loss of the PCs could be detected. Incubation of interleukin-1beta (IL-1β) was sufficient to mimic the electrophysiological alterations observed in EAE mice. We thus suggest that microglia and pro-inflammatory cytokines, together with a degeneration of basket and stellate cells and their synaptic terminals, contribute to impair GABAergic transmission on PCs during EAE. Our results support a growing body of evidence that GABAergic signaling is compromised in EAE and in MS, and show a selective susceptibility to neuronal and synaptic degeneration of cerebellar inhibitory interneurons.
authors.affiliation: Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello, 00143 Rome, Italy.
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grasselli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Antonietta
authors.initials: A
authors.lastname: Gentile
authors.forename: Gabriele
authors.initials: G
authors.lastname: Musumeci
authors.forename: Helena
authors.initials: H
authors.lastname: Sepman
authors.forename: Nabila
authors.initials: N
authors.lastname: Haji
authors.forename: Diego
authors.initials: D
authors.lastname: Fresegna
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D059330:GABAergic Neurons / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017729:Presynaptic Terminals / Q000473:pathology / Q000502:physiology; D011689:Purkinje Cells / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*