Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease

Neurobiol Dis. 2006 Jun;22(3):575-85. doi: 10.1016/j.nbd.2005.12.018. Epub 2006 Feb 17.


Batten disease, a lysosomal storage disorder, is caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3-/-) mouse model of the disease exhibits many characteristic pathological features of the human disorder. Here, we show that Cln3-/- mice, similarly to Batten disease patients, have a deficit in cerebellar motor coordination. To explore the possible cellular cause of this functional impairment, we compared the vulnerability of wild type (WT) and Cln3-/- cerebellar granule cell cultures to different toxic insults. We have found that cultured Cln3-/- cerebellar granule cells are selectively more vulnerable to AMPA-type glutamate receptor-mediated toxicity than their WT counterparts. This selective sensitivity was also observed in organotypic cerebellar slice cultures. Our results suggest that lack of the CLN3 protein has a significant influence on the function of AMPA receptors in cerebellar granule neurons, and that AMPA receptor dysregulation may be a major contributor to the cerebellar dysfunction in Batten disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death
  • Cell Survival
  • Cells, Cultured
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Cerebellum / physiopathology*
  • Disease Models, Animal
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Mutation
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Neuronal Ceroid-Lipofuscinoses / pathology
  • Neuronal Ceroid-Lipofuscinoses / physiopathology*
  • Neurons / metabolism
  • Neurons / pathology*
  • Organ Culture Techniques
  • Psychomotor Performance / physiology*
  • Receptors, AMPA / metabolism*


  • CLN3 protein, mouse
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Receptors, AMPA