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The Journal of Neuroscience, January 14, 2004, 24(2):508-513; doi:10.1523/JNEUROSCI.4386-03.2004

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Neurobiology of Disease
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, and Ian Parker

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4550

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 PS1 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 PS1_M146V 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 PS1_M146V mutations specifically disrupt intracellular Ca²⁺ 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 Ca²⁺ 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.

Key words: Alzheimer; calcium [Ca]; cortex; imaging; patch clamp; pyramidal; inositol triphosphate

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Received Sep 26, 2003; revised November 24, 2003; accepted November 25, 2003.

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