Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1.
Presenilins, whose mutant forms are the most common cause of early onset familial Alzheimer's disease, are involved in two very distinct processes: (i) proteolytic activity as gamma-secretase acting on amyloid precursor protein to produce amyloid peptides and (ii) storage of Ca2+ in the endoplasmic reticulum (ER). In particular, absence of presenilin-1 (PS1) was claimed to potentiate capacitative calcium entry (CCE), i.e. the mechanism of replenishment of ER Ca2+ stores. However, until now, evidence in favor of the latter role has been obtained only in isolated or cultured cells and not on neurons in situ. Here, we studied the strength of the synapses between Schaffer's collaterals and CA1 neurons in hippocampal slices when they were submitted first to Ca(2+)-free medium containing thapsigargin and subsequently to normal artificial cerebrospinal fluid, a procedure known to trigger CCE. We demonstrate that Ca2+ influx via the CCE mechanism is sufficient to trigger robust long term potentiation of the synapses in hippocampal slices from transgenic mice with a postnatal, neuron-specific ablation of PS1, but remarkably not from wild-type mice. Our data establish for the first time in neurons confined in normal neuronal networks that PS1 acts on the refilling mechanism of ER Ca2+ stores.
Ris
Laurence
L
Laboratory of Neuroscience, University of Mons-Hainaut, B-7000 Mons, Belgium.
Dewachter
Ilse
I
Reversé
Delphine
D
Godaux
Emile
E
Van Leuven
Fred
F
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002555:Cerebrospinal Fluid; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D053764:Presenilin-1; D013569:Synapses / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology
D008565:Membrane Proteins; D053764:Presenilin-1; D019284:Thapsigargin; D002118:Calcium