Kovács Attila D, Weimer Jill M, Pearce David A
Center for Aging and Developmental Biology, Aab Institute of Biomedical Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
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.
巴滕病是一种溶酶体贮积症，由CLN3基因突变引起。该疾病的Cln3基因敲除（Cln3-/-）小鼠模型表现出人类疾病的许多特征性病理特征。在此，我们表明，与巴滕病患者一样，Cln3-/-小鼠存在小脑运动协调缺陷。为了探究这种功能障碍可能的细胞原因，我们比较了野生型（WT）和Cln3-/-小脑颗粒细胞培养物对不同毒性损伤的易感性。我们发现，培养的Cln3-/-小脑颗粒细胞比野生型细胞对AMPA型谷氨酸受体介导的毒性更具选择性易感性。在小脑器官型切片培养物中也观察到了这种选择性敏感性。我们的结果表明，CLN3蛋白的缺失对小脑颗粒神经元中AMPA受体的功能有重大影响，并且AMPA受体失调可能是巴滕病小脑功能障碍的主要原因。
