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Dysregulated IP3Signaling in Cortical Neurons of Knock-In Mice Expressing an Alzheimer's-Linked Mutation in Presenilin1 Results in Exaggerated Ca2+Signals and Altered Membrane Excitability
Open accessAbstract
Disruptions in intracellular Ca 2+signaling are proposed to underlie the pathophysiology of Alzheimer's disease (AD), and it has recently been shown that AD-linked mutations in the presenilin 1 gene (PS1) enhance inositol triphosphate (IP 3)-mediated Ca 2+liberation in nonexcitable cells. However, little is known of these actions in neurons, which are the principal locus of AD pathology. We therefore sought to determine how PS1 mutations affect Ca 2+signals and their subsequent downstream effector functions in cortical neurons. Using whole-cell patch-clamp recording, flash photolysis, and two-photon imaging in brain slices from 4-5-week-old mice, we show that IP 3-evoked Ca 2+responses are more than threefold greater in PS1M146Vknock-in mice relative to age-matched nontransgenic controls. Electrical excitability is thereby reduced via enhanced Ca 2+activation of K+conductances. Action potential-evoked Ca 2+signals were unchanged, indicating that PS1M146Vmutations specifically disrupt intracellular Ca 2+liberation rather than reduce cytosolic Ca 2+buffering or clearance. Moreover, IP 3 receptor levels are not different in cortical homogenates, further suggesting that the exaggerated cytosolic Ca 2+signals may result from increased store filling and not from increased flux through additional IP 3-gated channels. Even in young animals,PS1 mutations have profound effects on neuronal Ca 2+and electrical signaling: cumulatively, these disruptions may contribute to the long-term pathophysiology of AD.
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Metadata
- Authors
- Stutzmann, G. E., Caccamo, A., LaFerla, F. M., & Parker, I.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-01-14
- Volume
- 24
- Issue
- 2
- Pages
- 508-513
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2142118492
- Cited by
- 278
- References
- 3
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
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