PT  - JOURNAL ARTICLE
AU  - Ellen Denayer
AU  - Tariq Ahmed
AU  - Hilde Brems
AU  - Geeske Van Woerden
AU  - Nils Zuiderveen Borgesius
AU  - Zsuzsanna Callaerts-Vegh
AU  - Akihiko Yoshimura
AU  - Dieter Hartmann
AU  - Ype Elgersma
AU  - Rudi D'Hooge
AU  - Eric Legius
AU  - Detlef Balschun
TI  - <em>Spred1</em> Is Required for Synaptic Plasticity and Hippocampus-Dependent Learning
AID  - 10.1523/JNEUROSCI.4698-08.2008
DP  - 2008 Dec 31
TA  - The Journal of Neuroscience
PG  - 14443--14449
VI  - 28
IP  - 53
4099  - http://www.jneurosci.org/content/28/53/14443.short
4100  - http://www.jneurosci.org/content/28/53/14443.full
SO  - J. Neurosci.2008 Dec 31; 28
AB  - 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.