. Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9458-62. PubMed.

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  1. Notch signaling plays a crucial role on cell fate specification during neuronal development in C. elegans, Drosophila and vertebrates. In the adult brain, however, the role of Notch signaling on neuronal morphology and function is largely unknown. Now, Wang et al. used Notch-1 antisense (NAS) transgenic mice expressing reduced levels of Notch-1 to demonstrate that Notch signaling is required for synaptic plasticity in the hippocampus, a brain region classically implicated in the acquisition of new memories. These authors found reduced maintenance of LTP and enhanced LTD in NAS-transgenic mice. Impaired LTP in hippocampal slices from NAS-transgenic mice was associated with reduced CBF1 activation, whereas incubation with the Notch ligand Jagged-1 increased Notch activity and LTP.

    This data linking Notch signaling and synaptic plasticity, together with recent findings from Alcino Silva’s lab (Costa et al., 2003; also see ARF related news story) showing memory deficits in Notch mutant mice, highlight, for the first time, the importance of the Notch signaling pathway for synaptic plasticity and learning and memory.

    These findings may be also relevant for Alzheimer’s disease (AD) because presenilin/γ-secretase facilitates the cleavage and release of the Notch intracellular domain (NICD), which is critical for Notch-mediated gene expression. Interestingly, familial AD mutations in presenilins and loss of PS function impair Notch-1 cleavage, raising the possibility that impaired Notch signaling may contribute to learning and memory deficits in familial AD. Whether mutations in PS may contribute to synaptic and memory impairments by affecting Notch signaling alone or in combination with other mechanisms (i.e., Aβ generation, protein trafficking, etc.) will need to be resolved in the future. While the synaptic and memory mechanisms regulated by presenilins are starting to be revealed, the present study contributes to our understanding of how altered PS activity may lead to cognitive dysfunction in AD.

    References:

    . Learning and memory deficits in Notch mutant mice. Curr Biol. 2003 Aug 5;13(15):1348-54. PubMed.

    View all comments by Carlos Saura

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  1. Notch and Memory: More Trouble for γ-Secretase Inhibition?