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The Journal of Neuroscience, July 9, 2008, 28(28):7091-7103; doi:10.1523/JNEUROSCI.0409-08.2008
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Neurobiology of Disease
Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control
Francesca Prestori,1 Paola Rossi,1 Bertrand Bearzatto,3 Jeanne Lainé,4 Daniela Necchi,2 Shyam Diwakar,1 Serge N. Schiffmann,3 Herbert Axelrad,4 andEgidio D'Angelo1 1Department of Molecular/Cellular Physiology and Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, and 2Department of Animal Biology, University of Pavia, 27100 Pavia, Italy, 3Laboratoire de Neurophysiologie (CP601), Faculté de Médecine, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium, and 4Laboratory of Cerebellar Neurobiology, Faculté de Médecine Pitiê-Salpétrière, 75013 Paris, France
Correspondence should be addressed to Egidio D'Angelo at the above address. Email: dangelo{at}unipv.it
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, when PrP 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 (Büeler et al., 1992). These results suggest that PrP plays an important role in granule cell development eventually regulating cerebellar network formation and motor control.
Key words: cerebellum; granule cell; prion; LTP; action potential; motor control
Received Feb. 24, 2007; revised May 20, 2008; accepted June 3, 2008.
Correspondence should be addressed to Egidio D'Angelo at the above address. Email: dangelo{at}unipv.it
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