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

• Main Authors: Attila D. Kovács, Jill M. Weimer, David A. Pearce
• Format: Article
• Language: English
• Published: Elsevier 2006-06-01
• Series: Neurobiology of Disease
• Subjects: Cerebellar granule cells; Cortical cultures; Cerebellar slice cultures; AMPA; Kainate; NMDA
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996105003645

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.