Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)

摘要: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3 that leads to vision loss, progressive cognitive and motor decline, premature death. Morphological evidence of astrocyte activation occurs early the process coincides with regions where neuronal loss eventually ensues. However, consequences on function remain relatively ill-defined. Astrocytes play critical role CNS homeostasis, part, their ability regulate extracellular milieu via formation extensive syncytial networks coupled gap junction (GJ) channels. In contrast, unopposed hemichannels (HCs) have been implicated pathology allowing non-discriminant passage molecules between intracellular milieus. Here we examined acute brain slices from mutant mice (CLN3Δex7/8) determine whether alters balance GJ HC activity. CLN3Δex7/8 displayed transient increases opening at postnatal day 30 numerous regions, compared wild type (WT) animals; however, activity steadily decreased days 60 90 astrocytes reach levels lower than WT cells. This suggested decline function, which was supported significant reductions glutamine synthetase, GLAST, connexin expression animals. Based increase activity, were treated novel carbenoxolone derivative INI-0602 inhibit HCs. Administration for one month period significantly reduced ceroid inclusions brains animals, coincided communication normalization resting membrane potential levels. Collectively, these findings suggest alterations may impact progression JNCL could offer therapeutic target.