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J. Biol. Chem., Vol. 282, Issue 2, 1119-1127, January 12, 2007

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Mutant Presenilin 1 Alters Synaptic Transmission in Cultured Hippocampal Neurons^*

Christina Priller, Ilse Dewachter, Neville Vassallo^¶, Sandra Paluch, Claudia Pace, Hans A. Kretzschmar, Fred Van Leuven, and Jochen Herms¹

From the Department of Neuropathology, Ludwig-Maximilians-Universität Munich, Feodor-Lynen-Strasse 23, 81377 München, Germany, the Experimental Genetics Group, KULeuven-Campus Gasthuisberg, B-3000 Leuven, Belgium, and the ^¶Department of Physiology and Biochemistry, University of Malta, Msida MSD06, Malta

Mutations in presenilins are the major cause of familial Alzheimer disease, but the precise pathogenic mechanism by which presenilin (PS) mutations cause synaptic dysfunction leading to memory loss and neurodegeneration remains unclear. Using autaptic hippocampal cultures from transgenic mice expressing human PS1 with the A246E mutation, we demonstrate that mutant PS1 significantly depressed the amplitude of evoked -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor-mediated synaptic currents. Analysis of the spontaneous miniature synaptic activity revealed a lower frequency of miniature currents but normal miniature amplitude. Both alterations could be rescued by the application of a -secretase blocker. On the other hand, the application of synthetic soluble A₄₂ in wild-type neurons induced the PS1 mutant phenotype on synaptic strength. Together, these findings strongly suggest that the expression of mutant PS1 in cultured neurons depresses synaptic transmission by causing a physical reduction in the number of synapses. This hypothesis is consistent with morphometic and semiquantitative immunohistochemical analysis, revealing a decrease in synaptophysin-positive puncta in PS1 mutant hippocampal neurons.

Received for publication, May 26, 2006 , and in revised form, October 31, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 596 and the Bayerische Forschungsverbunt ForPrion. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 89-2180-78010; Fax: 89-2180-78037; E-mail: jochen.herms{at}med.uni-muenchen.de.

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