Impairment of cerebellar long-term depression and GABAergic transmission in prion protein deficient mice ectopically...

Prion protein (PrP^C) knockout mice, named as the "Ngsk" strain (Ngsk Prnp^0/0 mice), show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrP^C-like protein (PrPLP/Dpl). Our previous study indicated that the mutant mice also exhibited alterations in cerebellum-dependent delay eyeblink conditioning, even at a young age (16 weeks of age) when neurological changes had not occurred. Thus, this electrophysiological study was designed to examine the synaptic function of the cerebellar cortex in juvenile Ngsk Prnp^0/0 mice. We showed that Ngsk Prnp^0/0 mice exhibited normal paired-pulse facilitation but impaired long-term depression of excitatory synaptic transmission at synapses between parallel fibres and PCs. GABA_A-mediated inhibitory postsynaptic currents recorded from PCs were also weakened in Ngsk Prnp^0/0 mice. Furthermore, we confirmed that Ngsk Prnp^0/0 mice (7-8-week-old) exhibited abnormalities in delay eyeblink conditioning. Our findings suggest that these alterations in both excitatory and inhibitory synaptic transmission to PCs caused deficits in delay eyeblink conditioning of Ngsk Prnp^0/0 mice. Therefore, the Ngsk Prnp^0/0 mouse model can contribute to study underlying mechanisms for impairments of synaptic transmission and neural plasticity, and cognitive deficits in the central nervous system.