Proposed relationship between astrocyte HC activity, brain metabolites, and neuronal loss in JNCL.

<p>Astrocyte HCs are transiently opened in numerous brain regions in the context of CLN3 mutation, which likely distorts the brain metabolome. This is supported by the ability of the HC inhibitor, INI-0602, to reduce lysosomal ceroid inclusions and enhance gap junction communication that is associated with the maintenance of homeostatic gradients in the CNS milieu. Previous studies have reported increases in ceramide, ATP, and glutamate in JNCL, the latter of which can be linked to HC action as well as the global decreases in glutamine synthetase and GLAST expression in CLN3^Δex7/8 mice. Collectively, these changes are suggestive of progressive loss of normal astrocyte homeostatic functions, which may contribute to neuronal loss in JNCL.