Author:

Keywords:

Spred1, hippocampus, learning, Morris water, maze, synaptic plasticity, LTP, LTD, Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Morris water maze, LONG-TERM POTENTIATION, ACTIVATED PROTEIN-KINASE, NEUROFIBROMATOSIS TYPE-1, MOUSE MODEL, DEFICITS, PATHWAY, ERK, DROSOPHILA, INHIBITOR, FREQUENCY, Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, Behavior, Animal, Biophysics, Dendrites, Discrimination Learning, Electric Stimulation, Electron Microscope Tomography, Extracellular Signal-Regulated MAP Kinases, Female, Hand Strength, Hippocampus, In Vitro Techniques, Learning, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Neurons, Pain Threshold, Photic Stimulation, Repressor Proteins, Silver Staining, Synaptic Potentials, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery, 3209 Neurosciences

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