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The Journal of Neuroscience, February 9, 2005, 25(6):1540-1549; doi:10.1523/JNEUROSCI.3850-04.2005

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Development/Plasticity/Repair
Presenilin Attenuates Receptor-Mediated Signaling and Synaptic Function

Angèle T. Parent, Natalie Y. Barnes, Yoshihito Taniguchi, Gopal Thinakaran, and Sangram S. Sisodia

Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637

Presenilin (PS) plays an essential role in intramembranous -secretase processing of amyloid precursor protein (APP) and several membrane-bound proteins. Here we report that selective accumulation of a membrane-tethered deleted in colorectal cancer (DCC) derivative (DCC-) correlates with extensive neurite outgrowth in transfected neuroblastoma cells and axodendritic connectivity associated with increased spine density in cortical neurons derived from PS1^-/- embryos, as well as wild-type neurons treated with -secretase inhibitors. cAMP-dependent signaling was also increased in both the neuroblastoma and cortical neuron systems. As a physiological consequence of increases in axodendritic connectivity and in the magnitude of cAMP-dependent signaling, short- and long-term glutamatergic synaptic transmission was enhanced in PS-deficient neurons. Together, these results demonstrate for the first time that PS-mediated -secretase activity attenuates receptor-mediated intracellular signaling pathways that are critical in regulating glutamatergic synaptic transmission and memory processes.

Key words: -secretase; Alzheimer's disease; deleted in colorectal cancer; glutamatergic synaptic transmission; cAMP/PKA pathway; neurite outgrowth

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Received Sep 16, 2004; revised December 30, 2004; accepted December 30, 2004.

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