Altered neuron excitability and synaptic plasticity in the cerebellar granular layer of juvenile prion protein knock-out mice with impaired motor control.

Although the role of abnormal prion protein (PrP) conformation in generating infectious brain diseases (transmissible spongiform
encephalopathy) has been recognized, the function of PrP in the normal brain remains mostly unknown. In this investigation, we
considered the effect of PrP gene knock-out (PrP0/0) on cerebellar neural circuits and in particular on granule cells, which show intense
PrP expression during development and selective affinity for PrP. At the third postnatal week,whenPrP expression would normally attain
mature levels, PrP0/0 mice showed low performance in the accelerating rotarod and runway tests and the functioning of 40% of granule
cells was abnormal. Spikes were slow, nonovershooting, and nonrepetitive in relation with a reduction in transient inward and outward
membrane currents, and also the EPSPs and EPSCs had slow kinetics. Overall, these alterations closely resembled an immature phenotype.
Moreover, in slow-spiking PrP0/0 granule cells, theta-burst stimulation was unable to induce any long-term potentiation. This
profound impairment in synaptic excitation and plasticity was associated with a protracted proliferation of granule cells and disappeared
at P40 –P50 along with the recovery of normal motor behavior (Bu¨eler et al., 1992). These results suggest that PrP plays an important role
in granule cell development eventually regulating cerebellar network formation and motor control.