title: Alzheimer's disease risk factor lymphocyte-specific protein tyrosine kinase regulates long-term synaptic strengthening, spatial learning and memory.
abstract: The lymphocyte-specific protein tyrosine kinase (Lck), which belongs to the Src kinase-family, is expressed in neurons of the hippocampus, a structure critical for learning and memory. Recent evidence demonstrated a significant downregulation of Lck in Alzheimer's disease. Lck has additionally been proposed to be a risk factor for Alzheimer's disease, thus suggesting the involvement of Lck in memory function. The neuronal role of Lck, however, and its involvement in learning and memory remain largely unexplored. Here, in vitro electrophysiology, confocal microscopy, and molecular, pharmacological, genetic and biochemical techniques were combined with in vivo behavioral approaches to examine the role of Lck in the mouse hippocampus. Specific pharmacological inhibition and genetic silencing indicated the involvement of Lck in the regulation of neuritic outgrowth. In the functional pre-established synaptic networks that were examined electrophysiologically, specific Lck-inhibition also selectively impaired the long-term hippocampal synaptic plasticity without affecting spontaneous excitatory synaptic transmission or short-term synaptic potentiation. The selective inhibition of Lck also significantly altered hippocampus-dependent spatial learning and memory in vivo. These data provide the basis for the functional characterization of brain Lck, describing the importance of Lck as a critical regulator of both neuronal morphology and in vivo long-term memory.
authors.affiliation: Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I, 1090, Vienna, Austria.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Monje
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Harald
authors.initials: H
authors.lastname: Höger
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Pollak
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D020868:Gene Silencing; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)