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 Ca oscillations were reduced in murine Cln3 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 astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3 astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3 astrocytes. Interestingly, despite these functional deficits in Cln3 astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca signaling, murine Cln3 neurons were hyper-responsive to glutamate, as reflected by heightened and prolonged Ca signals. These findings identify intrinsic metabolic and Ca signaling defects in Cln3 astrocytes that may contribute to neuronal dysfunction in CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".