Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease.
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.
Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Attila D
AD
Kovács
Jill M
JM
Weimer
David A
DA
Pearce
D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009924:Organ Culture Techniques; D011597:Psychomotor Performance / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism*
C102229:CLN3 protein, mouse; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018091:Receptors, AMPA