MEMORY IMPAIRMENT IN NIEMANN-PICK C DISEASE: AMELIORATING EFFECTS OF MIGLUSTAT.

Niemann–Pick Type C disease (NPC) is an autosomal recessive fatal disorder caused by mutations in the NPC1 gene. NPC shows abnormal intracellular accumulation of cholesterol and gangliosides associated with peripheral and central organ dysfunction. Among the neurological symptoms are ataxia and cognitive decline until severe dementia. Although the genetic defects causing NPC are well known, very little information is available on the causes of neurological deficits and neuropathology. . Changes in the plasma membrane cholesterol content and in the glycosphingolipids/cholesterol ratio is particularly important in affecting lipid rafts and neurotransmitter receptor activity: in particular, lipid rafts are important regulators of glutamate receptor functioning. Miglustat (Zavesca®, Actelion Pharmaceuticals), a drug initially used in the treatment of several glycosidosis including GM1 gangliosidosis, Gaucher type I and Tay-Sachs disease, is now under trial in different medical centers, representing a promising therapeutic approach for the NPC therapy. In this study we evaluated: i) basal synaptic transmission and synaptic plasticity phenomena, involved in learning and memory processes, in NPC mice, a well-established mouse model for the Niemann-Pick type C disease; ii) Miglustat ability in ameliorating the cognitive impairment associated with NPC. To this aim we used acute brain slices and primary neuronal cell cultures from NPC and wild type (WT) mice, treated by oral administration (gavage) for 14 days with Miglustat (0,2 mg/kg) or saline solution. Our results show that in untreated NPC mice slices induction and maintenance of long-term potentiation (LTP) in the CA1 hippocampal region were impaired whereas basal synaptic transmission and paired pulse facilitation (PPF) were not affected. In line with these observations, we found a significantly reduction in NMDA-induced calcium influx in NPC cultured hippocampal neurons as compared with WT neurons. Furthermore, mice slices from Miglustat-treated NPC animals showed a significant recovery of both induction and maintenance of LTP. On the contrary, Miglustat treatment did not affect basal synaptic transmission and PPF in both NPC and WT mice. Further studies will be performed to elucidate the mechanisms of action of Miglustat on excitatory transmission and receptor function.