Spred1 is required for synaptic plasticity and hippocampus-dependent learning.
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.
Denayer
Ellen
E
Department of Human Genetics and Laboratory of Biological Psychology, University of Leuven, B-3000 Leuven, Belgium.
Ahmed
Tariq
T
Brems
Hilde
H
Van Woerden
Geeske
G
Borgesius
Nils Zuiderveen
NZ
Callaerts-Vegh
Zsuzsanna
Z
Yoshimura
Akihiko
A
Hartmann
Dieter
D
Elgersma
Ype
Y
D'Hooge
Rudi
R
Legius
Eric
E
Balschun
Detlef
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001703:Biophysics; D003712:Dendrites / Q000648:ultrastructure; D004193:Discrimination Learning / Q000502:physiology; D004558:Electric Stimulation; D055032:Electron Microscope Tomography / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D018737:Hand Strength / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000648:ultrastructure; D017288:Pain Threshold / Q000502:physiology; D010775:Photic Stimulation / Q000379:methods; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016622:Silver Staining / Q000379:methods; D055366:Synaptic Potentials / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C433763:Spred1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases