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The Journal of Neuroscience, December 31, 2008, 28(53):14443-14449; doi:10.1523/JNEUROSCI.4698-08.2008

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Neurobiology of Disease
Spred1 Is Required for Synaptic Plasticity and Hippocampus-Dependent Learning

Ellen Denayer,^1 * Tariq Ahmed,^2 * Hilde Brems,^1 * Geeske Van Woerden,³ Nils Zuiderveen Borgesius,³ Zsuzsanna Callaerts-Vegh,² Akihiko Yoshimura,^4,5 Dieter Hartmann,⁶ Ype Elgersma,³ Rudi D'Hooge,² Eric Legius,¹ and Detlef Balschun²

¹Department of Human Genetics and ²Laboratory of Biological Psychology, University of Leuven, B-3000 Leuven, Belgium, ³Department of Neuroscience, Erasmus MC–University Medical Center, 3000 CA Rotterdam, The Netherlands, ⁴Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, ⁵Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan, and ⁶Anatomisches Institut der Universität Bonn, D-53115 Bonn, Germany

Correspondence should be addressed to either of the following: Dr. Eric Legius or Dr. Detlef Balschun, University of Leuven, B-3000 Leuven, Belgium. Email: eric.legius{at}uz.kuleuven.ac.be or Email: detlef.balschun{at}psy.kuleuven.be

Germline mutations in SPRED1, a negative regulator of Ras, have been described in a neurofibromatosis type 1 (NF1)-like syndrome (NFLS) that included learning difficulties in some affected individuals. NFLS belongs to the group of phenotypically overlapping neuro-cardio-facial-cutaneous syndromes that are all caused by germ line mutations in genes of the Ras/mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) pathway and that present with some degree of learning difficulties or mental retardation. We investigated hippocampus-dependent learning and memory as well as synaptic plasticity in Spred1^–/– mice, an animal model of this newly discovered human syndrome. Spred1^–/– mice show decreased learning and memory performance in the Morris water maze and visual-discrimination T-maze, but normal basic neuromotor and sensory abilities. Electrophysiological recordings on brain slices from these animals identified defects in short- and long-term synaptic hippocampal plasticity, including a disequilibrium between long-term potentiation (LTP) and long-term depression in CA1 region. Biochemical analysis, 4 h after LTP induction, demonstrated increased ERK-phosphorylation in Spred1^–/– slices compared with those of wild-type littermates. This indicates that deficits in hippocampus-dependent learning and synaptic plasticity induced by SPRED1 deficiency are related to hyperactivation of the Ras/ERK pathway.

Key words: Spred1; hippocampus; learning; Morris water maze; synaptic plasticity; LTP; LTD

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Received Sept. 30, 2008; revised Nov. 18, 2008; accepted Nov. 21, 2008.

Correspondence should be addressed to either of the following: Dr. Eric Legius or Dr. Detlef Balschun, University of Leuven, B-3000 Leuven, Belgium. Email: eric.legius{at}uz.kuleuven.ac.be or Email: detlef.balschun{at}psy.kuleuven.be

This article has been cited by other articles:

				L. Messiaen, S. Yao, H. Brems, T. Callens, A. Sathienkijkanchai, E. Denayer, E. Spencer, P. Arn, D. Babovic-Vuksanovic, C. Bay, et al. Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome JAMA, November 18, 2009; 302(19): 2111 - 2118. [Abstract] [Full Text] [PDF]

				E Pasmant, A Sabbagh, N Hanna, J Masliah-Planchon, E Jolly, P Goussard, P Ballerini, F Cartault, S Barbarot, J Landman-Parker, et al. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype J. Med. Genet., July 1, 2009; 46(7): 425 - 430. [Abstract] [Full Text] [PDF]

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