Astrocytes in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3) Display Metabolic and Calcium Signaling Abnormalities

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in ceroid lipofuscinosis 3 (CLN3). Children with JNCL experience progressive visual, cognitive, and motor deterioration with a decreased life expectancy (late teens-early 20s). Neuronal loss is thought to occur, in part, via glutamate excitotoxicity; however, little is known about astrocyte glutamate regulation in JNCL. Spontaneous Ca2+ oscillations were reduced in murine Cln3(Delta ex7/8) astrocytes, which were also observed following glutamate or cytokine exposure. Astrocyte glutamate transport is an energy-demanding process and disruptions in metabolic pathways could influence glutamate homeostasis in Cln3(Delta ex7/8) astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3(Delta ex7/8) astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3(Delta ex7/8) astrocytes. Interestingly, despite these functional deficits in Cln3(Delta ex7/8) astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca2+ signaling, murine Cln3(Delta ex7/8) neurons were hyper-responsive to glutamate, as reflected by heightened and prolonged Ca2+ signals. These findings identify intrinsic metabolic and Ca2+ signaling defects in Cln3(Delta ex7/8) astrocytes that may contribute to neuronal dysfunction in CLN3 disease. .