Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1

Neurobiol Dis. 2021 Jul;154:105340. doi: 10.1016/j.nbd.2021.105340. Epub 2021 Mar 19.


Bergmann glia (BG) are highly specialized radial astrocytes of the cerebellar cortex, which play a key role in the uptake of synaptic glutamate via the excitatory amino acid transporter EAAT1. Multiple lines of evidence suggest that in cerebellar neurodegenerative diseases reactive BG has a negative impact on neuronal function and survival through compromised EAAT activity. A family of such diseases are those caused by expansion of CAG repeats in genes of the ataxin family, resulting in spinocerebellar ataxias (SCA). We investigated the contribution of BG to the pathogenesis of cerebellar neurodegeneration in a model of SCA1, which was induced by expression of a polyglutamine mutant of ataxin-1 (ATXN1[Q85]) in BG specifically. We compared the outcomes with a novel model where we triggered excitotoxicity by a chronic optogenetic activation of BG with channelrhodopsin-2 (ChR2). In both cases we detected evidence of reduced glutamate uptake manifested by prolongation of excitatory postsynaptic currents in Purkinje cells which is consistent with documented reduction of expression and/or function of EAAT1. In both models we detected astroglyosis and Purkinje cells atrophy. Finally, the same pattern was detected in a knock-in mouse which expresses a polyglutamine mutant ataxin-1 ATXN1[Q154] in a non-cell-selective manner. Our results suggest that ATXN1[Q85] and ChR2-induced insult targeted to BG closely mimics SCA1 pathology, where excessive glutamate signaling appears to be a common feature likely being an important contributor to cerebellar neurodegeneration.

Keywords: Bergmann glia; Cerebellum; Excitatory amino acid transporter type 1; Purkinje cell; Spinocerebellar ataxia type 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-1 / biosynthesis*
  • Ataxin-1 / genetics
  • Cell Death / physiology
  • Excitatory Amino Acid Transporter 1 / antagonists & inhibitors*
  • Excitatory Amino Acid Transporter 1 / biosynthesis*
  • Excitatory Amino Acid Transporter 1 / genetics
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Optogenetics / adverse effects*
  • Photic Stimulation / adverse effects
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology


  • Ataxin-1
  • Atxn1 protein, mouse
  • Excitatory Amino Acid Transporter 1
  • Slc1a3 protein, mouse