Cerebellar synaptogenesis is compromised in mouse models of DYT1 dystonia

Valentina Vanni, Francesca Puglisi, Paola Bonsi, Giulia Ponterio, Marta Maltese, Antonio Pisani, Georgia Mandolesi

Research output: Contribution to journalArticlepeer-review


Early-onset torsion dystonia (DYT1) is an autosomal-dominant movement disorder characterized by sustained muscle contractions and abnormal posturing. It is caused by a three base-pair deletion (δGAG) in the gene encoding the AAA+ protein torsinA, which gives rise to a loss of function mutation responsible of neuronal functional abnormalities. Symptoms typically appear during childhood, suggesting the presence of an early critical period of sensorimotor circuit susceptibility to torsinA dysfunction. Here, we identified in two different DYT1 mouse strains, heterozygous torsinA knockout mice (Tor1a+/-) and human δGAG mutant torsinA transgenic mice (hMT), the anatomical abnormalities in the cerebellum, during a critical age for synaptogenesis (postnatal day 14, P14). By means of immunofluorescence, confocal analysis and western blot quantification, we observed a reduced inhibitory input on Purkinje cells (PCs) as well as an unbalanced excitatory innervation; a significant reduction of the parallel fiber (PF) synaptic terminals and an increase of the climbing fiber (CF) inputs. Finally, in support of the in vivo results, we also provide evidence of an impaired PF synaptogenesis in a co-culture system. Of note, these alterations were rescued and in part over-compensated in the adult age in both mouse strains, suggesting that torsinA dysfunction can induce an altered maturation of cerebellar synaptic contacts. Altogether these results indicate that a loss of function of torsinA during cerebellar synaptogenesis induces important developmental alterations, that might contribute to the age-dependent susceptibility to develop dystonia in mutation carriers.

Original languageEnglish
Pages (from-to)457-467
Number of pages11
JournalExperimental Neurology
Publication statusPublished - Sep 1 2015


  • Cerebellum
  • Development
  • DYT1 dystonia
  • GABAergic synapse
  • Glutamatergic synapse
  • Purkinje cells
  • Synaptogenesis
  • δGAG mutant torsinA

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Medicine(all)

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