Spred1 is required for synaptic plasticity and hippocampus-dependent learning

Ellen Denayer, Tariq Ahmed, Hilde Brems, Geeske Van Woerden, Nils Zuiderveen Borgesius, Zsuzsanna Callaerts-Vegh, Akihiko Yoshimura, Dieter Hartmann, Ype Elgersma, Rudi D'Hooge, Eric Legius, Detlef Balschun

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65 Citations (Scopus)

Abstract

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 neurocardio-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 hippocampusdependent learning and synaptic plasticity induced by SPRED1 deficiency are related to hyperactivation of the Ras/ERK pathway.

Original languageEnglish
Pages (from-to)14443-14449
Number of pages7
JournalJournal of Neuroscience
Volume28
Issue number53
DOIs
Publication statusPublished - 31 Dec 2008

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Keywords

  • Hippocampus
  • LTD
  • LTP
  • Learning
  • Morris water maze
  • Spred1
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Denayer, E., Ahmed, T., Brems, H., Van Woerden, G., Borgesius, N. Z., Callaerts-Vegh, Z., Yoshimura, A., Hartmann, D., Elgersma, Y., D'Hooge, R., Legius, E., & Balschun, D. (2008). Spred1 is required for synaptic plasticity and hippocampus-dependent learning. Journal of Neuroscience, 28(53), 14443-14449. https://doi.org/10.1523/JNEUROSCI.4698-08.2008