Altered Intracellular Calcium Homeostasis in Cerebellar Granule Cells of Prion Protein‐Deficient Mice

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

“…In addition to the arrival of new immature granule cells, other PrP-dependent mechanisms may be altered in granule cells once migration is concluded. A reduced L-type Ca 2ϩ -channel expression, which was observed in PrP 0/0 granule cells in culture (Herms et al, 2000;Fuhrmann et al, 2006) (see also Korte et al, 2003), could reduce spike afterhyperpolarization by weakening activation of calcium-dependent K-channels (Colling et al, 1996;Herms et al, 2001) and contribute to alter repetitive spike discharge.…”

“…In fact, membrane depolarization during TBS was larger in slow-spiking PrP 0/0 than in fastspiking granule cells, and the slow time course of NMDA EPSCs suggests that Ca 2ϩ influx, which is needed for LTP induction (D'Angelo et al, 1999;Armano et al, 2000;Rossi et al, 2002;Gall et al, 2005), might be even larger in PrP 0/0 than in wild type. Therefore, the mechanisms of dysfunction may involve alterations in intracellular Ca 2ϩ dynamics, which have been reported in PrP 0/0 cultured cerebellar granule cells (Herms et al, 2000). A defect in nitric oxide signaling (Keshet et al, 1999), which is required for mossy fiber-granule cell LTP (Maffei et al, 2003), could explain the absence of presynaptic changes needed to generate EPSC potentiation (Sola et al, 2004).…”

“…Recordings from brain slices of PrP 0/0 mice showed reduced synaptic inhibition and long-term potentiation (LTP) (a neural correlate of learning) (Bliss and Collingridge, 1993) in the hippocampus (Collinge et al, 1994;Curtis et al, 2003;Maglio et al, 2004Maglio et al, , 2006, but this observation was not confirmed (Lledo et al, 1996). Several abnormalities have been observed in PrP 0/0 neurons in culture, including reduced Ca 2ϩ -dependent K ϩ currents (Colling et al, 1996;Herms et al, 2001;Mallucci et al, 2002) and cytoplasmic Ca 2ϩ levels (Herms et al, 2000). PrP is distributed on the neuron surface and in presynaptic terminals (Herms et al, 1999;Ferrer et al, 2000).…”

The Prion Protein and Its Paralogue Doppel Affect Calcium Signaling in Chinese Hamster Ovary Cells

“…Also, in analogy with SOCCs modulation of transmitter release and synaptic plasticity in certain neurons (Emptage et al, 2001), PrP celicited Ca 2ϩ hotspots may recruit effectors in the immediate vicinity, e.g., Ca 2ϩ -activated K ϩ channels, thereby explaining why impairment of (Ca 2ϩ -dependent) K ϩ currents in PrP-null cells could not be attributed to specific alterations of voltage-gated Ca 2ϩ channels (Herms et al, 2000; but see Whatley et al, 1995). In the light of all these considerations, it is thus tempting to speculate that, as observed in the used cell model system, PrP c affects SOCC-dependent subplasma membrane Ca 2ϩ pools also in neurons.…”

“…Importantly, other data from electrophysiologic studies, and/or cell Ca 2ϩ measurements, converge in supporting that PrP c absence, or its recruitment into prions, leads to a compromised Ca 2ϩ homeostasis and that such a defect ultimately impinges on a few Ca 2ϩ -dependent neurophysiologic functions, such as plasma membrane K ϩ currents, after-hyperpolarization potential (AHP) and depolarizing after-potential (DAP) events (Jefferys et al, 1994;Colling et al, 1996;Johnston et al, 1998;Barrow et al, 1999;Herms et al, 2000Herms et al, , 2001Mallucci et al, 2002).…”