title: Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices.
abstract: Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid beta-peptide (Abeta). However, Abeta-independent effects of mutant PS1 on neuronal Ca(2+) homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca(2+)chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.
authors: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Gerontology Research Center, Baltimore, MD 21224, USA. wangyu@grc.nia.nih.gov
authors: Yue
authors: Y
authors: Wang
authors: Nigel H
authors: NH
authors: Greig
authors: Qian-sheng
authors: QS
authors: Yu
authors: Mark P
authors: MP
authors: Mattson
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000378:metabolism / Q000503:physiopathology; D002799:Cholinergic Fibers / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000235:genetics*; D009924:Organ Culture Techniques; D053764:Presenilin-1 / Q000235:genetics*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D053764:Presenilin-1; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D000109:Acetylcholine