Journal
JOURNAL OF NEUROSCIENCE
Volume 28, Issue 53, Pages 14443-14449Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4698-08.2008
Keywords
Spred1; hippocampus; learning; Morris water maze; synaptic plasticity; LTP; LTD
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Funding
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen [G.0578.06, G.0551.08, G.0496.07, G.0327.08]
- Katholieke Universiteit ( K. U.) Leuven Impulse Programme
- K. U. Leuven Research [OT/06/23]
- Federal Office for Scientific, Technical, and Cultural Affairs, Belgium [P6/05]
- K. U. Leuven
- Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation [07-4]
- Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen)
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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 hippocampus-dependent learning and synaptic plasticity induced by SPRED1 deficiency are related to hyperactivation of the Ras/ERK pathway.
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