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Previous neurophysiological studies on prion protein deficient ( Prnp –/–) mice have revealed a significant reduction of slow afterhyperpolarization currents (s IAHP) in hippocampal CA1 pyramidal cells. Here we aim to determine whether loss of PrPC. directly affects the potassium channels underlying s IAHP or if s IAHP is indirectly disturbed by altered intracellular Ca2+ fluxes. Patch-clamp measurements and confocal Ca2+ imaging in acute hippocampal slice preparations of Prnp –/– mice compared to littermate control mice revealed a reduced Ca2+ rise in CA1 neurons lacking PrPC following a depolarization protocol known to induce s IAHP. Moreover, we observed a reduced Ca2+ influx vial-type voltage gated calcium channels (VGCCs). No differences were observed in the protein expression of the pore forming α1 subunit of VGCCs Prnp –/– mice. Surprisingly, the β2 subunit, critically involved in the transport of the α1 subunit to the plasma membrane, was found to be up-regulated in knock out hippocampal tissue. On mRNA level however, no differences could be detected for the α1C, D and β2–4 subunits. In conclusion our data support the notion that lack of PrPC. does not directly affect the potassium channels underlying s IAHP, but modulates these channels due to its effect on the intracellular free Ca2+ concentration via a reduced Ca2+ influx throughl-type VGCCs. [ABSTRACT FROM AUTHOR]

Mutations in presenilins are the major cause of familial Alzheimer's disease (FAD), leading to impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Presenilins are the catalytic subunits of γ-secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two-photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over-expressing either human wild-type PS1 or the FAD-mutated variant A246E (FAD-PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over-expressing human wild-type presenilin1 and FAD-PS1, whereas on basal layer 3 dendrites only over-expression of FAD-PS1 increased the spine density. Time-lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ-secretase-dependent processing of synapse-relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca(2+) homeostasis in PS1 over-expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain-of-function but γ-secretase-independent manner., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)