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Alzheimer’s disease risk factor lymphocyte-specific protein tyrosine kinase regulates long-term synaptic strengthening, spatial learning and memory

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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.

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Acknowledgments

We thank Ing. Reiner Poldi, the NPI Company and Dr. Gerhard Rammes for expert support during the implementation of the electrophysiological techniques. F.J.M. received financial support from the Hochschul-Jubiläum-Stiftung der Stadt Wien.

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Authors and Affiliations

  1. Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I, 1090, Vienna, Austria

    Eun-Jung Kim, Francisco J. Monje & Daniela D. Pollak

  2. Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Eun-Jung Kim, Lin Li & Gert Lubec

  3. Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna, Brauhausgasse 34, 2325, Himberg, Austria

    Harald Höger

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  1. Eun-Jung Kim
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  2. Francisco J. Monje
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Correspondence to Gert Lubec.

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E.-J. Kim and F. J. Monje equally shared authorship.

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Kim, EJ., Monje, F.J., Li, L. et al. Alzheimer’s disease risk factor lymphocyte-specific protein tyrosine kinase regulates long-term synaptic strengthening, spatial learning and memory. Cell. Mol. Life Sci. 70, 743–759 (2013). https://doi.org/10.1007/s00018-012-1168-1

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