Deficient mitochondrial Ca(2+) buffering in the Cln8(mnd) mouse model of neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) are a group of genetic childhood-onset progressive brain diseases characterized by a decline in mental and motor capacities, epilepsy, visual loss and premature death. Using patch clamp, fluorescence imaging and caged Ca(2+) photolysis, we evaluated the mechanisms of neuronal Ca(2+) clearance in Cln8(mnd) mice, a model of the human NCL caused by mutations in the CLN8 gene. In Cln8(mnd) hippocampal slices, Ca(2+) clearance efficiency in interneurons and, to some extent, principal neurons declined with age. In cultured Cln8(mnd) hippocampal neurons, clearance of large Ca(2+) loads was inefficient due to impaired mitochondrial Ca(2+) uptake. In contrast, neither Ca(2+) uptake by sarco/endoplasmic reticulum Ca(2+) ATPase, nor Ca(2+) extrusion through plasma membrane was affected by the Cln8 mutation. Excitotoxic glutamate challenge caused Ca(2+) deregulation more readily in Cln8(mnd) than in wt neurons. We propose that neurodegeneration in human CLN8 disorders is primarily caused by reduced mitochondrial Ca(2+) buffering capacity.