Current knowledge about the molecular mechanisms of NMDA receptor (NMDAR)-independent long-term potentiation (LTP) in the hippocampus and its function for memory formation in the behaving animal is limited. NMDAR-independent LTP in the CA1 region is thought to require activity of postsynaptic L-type voltage-dependent Ca2+channels (Cav1.x), but the underlying channel isoform remains unknown. We evaluated the function of the Cav1.2 L-type Ca2+channel for spatial learning, synaptic plasticity, and triggering of learning-associated biochemical processes using a mouse line with an inactivation of theCACNA1C(Cav1.2) gene in the hippocampus and neocortex (Cav1.2HCKO). This model shows (1) a selective loss of protein synthesis-dependent NMDAR-independent Schaffer collateral/CA1 late-phase LTP (L-LTP), (2) a severe impairment of hippocampus-dependent spatial memory, and (3) decreased activation of the mitogen-activated protein kinase (MAPK) pathway and reduced cAMP response element (CRE)-dependent transcription in CA1 pyramidal neurons. Our results provide strong evidence for a role of L-type Ca2+channel-dependent, NMDAR-independent hippocampal L-LTP in the formation of spatial memory in the behaving animal and for a function of the MAPK/CREB (CRE-binding protein) signaling cascade in linking Cav1.2 channel-mediated Ca2+influx to either process.

Abstract-The role of T-type Ca 2ϩ channels for cardiovascular physiology, in particular blood pressure regulation, is controversial. Selective blockade of T-type Ca 2ϩ channels in resistance arteries has been proposed to explain the effect of the antihypertensive drug mibefradil. In the present study, we used a third generation, time-and tissue-specific conditional knockout model of the L-type Ca 2ϩ channel Ca v 1.2 (Ca v 1.2 SMAKO mice) to genetically dissect the effects of mibefradil on T-and L-type Ca 2ϩ channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Ca v 1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38Ϯ2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in

involved in the transport of the a1 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 a1C, D and b2-4 subunits. In conclusion our data support the notion that lack of PrP C.does not directly affect the potassium channels underlying sI AHP , but modulates these channels due to its effect on the intracellular free Ca 2+ concentration via a reduced Ca 2+ influx through L-type VGCCs.

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