ALTERED BRAIN EXCITABILITY IN NIEMANN PICK TYPE C DISEASE

Niemann-Pick Type C disease (NPC) is caused by mutations in the cholesterol transport protein Npc1, which lead to the endolysosomal accumulation of this lipid, causing a broad spectrum of neurological symptoms, including cognitive and psychiatric alterations as well as epilepsy. Using the Npc1^nmf164 mouse model for this disease, we are investigating the causes and assessing treatment options for these symptoms. Previous results from our laboratory found cholesterol buildup in endolysosomes to cause neurotransmitter receptor trafficking and synaptic plasticity abnormalities. To understand the impact in brain excitability we have measured hippocampal brain oscillations. We found strong deficiencies of power in Npc1^nmf164 mice compared to wild type mice, particularly in the theta rhythm and ripples. These abnormalities became especially apparent in the CA1 pyramidal layer, possibly pointing to defects in hippocampal pyramidal neurons, but appeared also in other layers, such as the stratum lacunosum. Concurrently, we have explored the epileptic phenotype by inducing seizures pharmacologically. We found Npc1^nmf164 mice to be more susceptible to epilepsy, a phenotype of abnormal neuronal activity coherent with our findings, which can be rescued via potentiation of the endocannabinoid system. Altogether, these results add valuable information on the alterations in brain excitability caused by deficiency of the cholesterol transport protein Npc1, and provide new therapeutic approaches that might help patients suffering from a devastating disease such as NPC.