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 language | English |
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Pages (from-to) | 14443-14449 |
Number of pages | 7 |
Journal | Journal of Neuroscience |
Volume | 28 |
Issue number | 53 |
DOIs | |
Publication status | Published - 2008 Dec 31 |
Keywords
- Hippocampus
- LTD
- LTP
- Learning
- Morris water maze
- Spred1
- Synaptic plasticity
ASJC Scopus subject areas
- Neuroscience(all)