GABAergic signaling and connectivity on Purkinje cells are impaired in experimental autoimmune encephalomyelitis

Georgia Mandolesi, Giorgio Grasselli, Alessandra Musella, Antonietta Gentile, Gabriele Musumeci, Helena Sepman, Nabila Haji, Diego Fresegna, Giorgio Bernardi, Diego Centonze

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)414-424
Number of pages11
JournalNeurobiology of Disease
Volume46
Issue number2
DOIs
Publication statusPublished - May 2012

Keywords

  • Cerebellar interneurons
  • EAE
  • IL1-beta
  • IPSC
  • Multiple sclerosis
  • Parvalbumin
  • PC
  • VGAT

ASJC Scopus subject areas

  • Neurology

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