Dysregulated IP3 Signaling in Cortical Neurons of Knock-In Mice Expressing an Alzheimer's-Linked Mutation in Presenilin1 Results in Exaggerated Ca2+ Signals and Altered Membrane Excitability

Grace E. Stutzmann, Antonella Caccamo, Frank M. LaFerla, Ian Parker

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

Disruptions in intracellular Ca2+ 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 (IP3)-mediated Ca2+ 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 PSI mutations affect Ca2+ 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 IP3-evoked Ca2+ responses are more than threefold greater in PS1M146V knock-in mice relative to age-matched nontransgenic controls. Electrical excitability is thereby reduced via enhanced Ca2+ activation of K+ conductances. Action potential-evoked Ca2+ signals were unchanged, indicating that PS1M146V mutations specifically disrupt intracellular Ca 2+ liberation rather than reduce cytosolic Ca2+ buffering or clearance. Moreover, IP3 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 IP3-gated channels. Even in young animals, PS1 mutations have profound effects on neuronal Ca2+ and electrical signaling: cumulatively, these disruptions may contribute to the long-term pathophysiology of AD.

Original languageEnglish (US)
Pages (from-to)508-513
Number of pages6
JournalJournal of Neuroscience
Volume24
Issue number2
DOIs
StatePublished - Jan 14 2004

Keywords

  • Alzheimer
  • Calcium [Ca]
  • Cortex
  • Imaging
  • Inositol triphosphate
  • Patch clamp
  • Pyramidal

ASJC Scopus subject areas

  • Neuroscience(all)

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