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.
Kovács
Attila D
AD
Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Weimer
Jill M
JM
Pearce
David A
DA
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