Cerebellar synaptogenesis is compromised in mouse models of DYT1 dystonia

Exp Neurol. 2015 Sep;271:457-67. doi: 10.1016/j.expneurol.2015.07.005. Epub 2015 Jul 14.

Abstract

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.

Keywords: Cerebellum; DYT1 dystonia; Development; GABAergic synapse; Glutamatergic synapse; Purkinje cells; Synaptogenesis; ΔGAG mutant torsinA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cerebellum / pathology*
  • Coculture Techniques
  • Disease Models, Animal
  • Dystonia / genetics
  • Dystonia / pathology*
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics*
  • Mutation / genetics*
  • Neurogenesis / genetics*
  • Neurons / pathology
  • Receptors, Glutamate / metabolism
  • Synapses / metabolism*
  • Vesicular Glutamate Transport Protein 1 / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Molecular Chaperones
  • Receptors, Glutamate
  • TOR1A protein, human
  • Vesicular Glutamate Transport Protein 1
  • glutamate receptor delta 2
  • gamma-Aminobutyric Acid