Editors' ChoiceNeuroscience

Presenilin Lets the Ca2+ Out of the Bag

Sci. Signal.  17 Sep 2013:
Vol. 6, Issue 293, pp. ec219
DOI: 10.1126/scisignal.2004725

As many as 90% of patients with familial Alzheimer’s disease (fAD) have mutations in presenilin (PS) genes. A defect in the processing of amyloid precursor protein by PS-mediated γ-secretase activity is likely a major contributor to the pathogenesis of fAD, but Wu et al. report another mechanism involving ryanodine receptors (RyRs), which are a family of ligand-gated channels at the endoplasmic reticulum (ER) (see D’Adamio and Castillo). Stimulation of RyRs releases calcium from the ER into the cytosol, which can augment calcium that enters through voltage-gated channels in the plasma membrane to promote presynaptic vesicle exocytosis. Wu et al. used cultured primary neurons and acute brain slices from mice with conditional ablation of PS1 and PS2 in the CA3 region of the hippocampus (PS-cDKO) to show that synaptic potentiation was compromised but that loss of PS in cultured neurons did not affect baseline calcium concentrations in the ER or the abundance of SERCA [the sarco-ER calcium adenosine triphosphatase (ATPase)], the ER calcium ATPase, or the ligand-gated, ER-localized calcium channel IP3R1 (inositol 1,4,5-trisphosphate receptor). Instead, analysis of the CA3 region from PS-cDKO mouse brain slices showed reduced binding of [3H]ryanodine. In hippocampal neurons cultured from the PS-cDKO mice, the abundance of RyRs; the ability of the RyR agonists, caffeine, and 4-chloro-m-cresol to induce ER calcium release; and caffeine-mediated potentiation of field excitatory postsynaptic potentials (fEPSP) were reduced. Dantrolene, a RyR inhibitor, reduced caffeine-mediated potentiation of fEPSPs in control neurons but not in PS-cDKO neurons. Lentiviral infection of hippocampal neurons with two independent short-hairpin RNAs targeting all three RyRs reduced RyR abundance to a similar degree as that in PS-cDKO neurons and inhibited increases in intracellular calcium induced by caffeine or exposure to high concentrations of potassium. Moreover, electrophysiological measurements of individual neurons in which RyR was knocked down or those from the PS-cDKO mice indicated that frequency facilitation at the synapse was disrupted. Given that fAD patients demonstrate reduced cognitive functions related to defects in synaptic potentiation, these findings could provide new insight into how mutations in PS contribute to the disease.

B. Wu, H. Yamaguchi, F. A. Lai, J. Shen, Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 110, 15091–15096 (2013).[Abstract][Full Text]

L. D’Adamio, P. E. Castillo, Presenilin-ryanodine receptor connection. Proc. Natl. Acad. Sci. U.S.A. 110, 14825–14826 (2013).[Full Text]