Sensory stimulation increases cortical expression of the fragile X mental retardation protein in vivo.

Fragile X syndrome is a common cause of mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), an RNA binding protein whose function remains unclear. Recent in vitro work has demonstrated that the protein is translated near the synapse in an activity dependent manner [33]. We therefore asked whether expression of FMRP might be altered by neuronal activity in vivo. Using immunoblots of different sub-cellular fractions of the rat somatosensory cortex, we show that the levels of FMRP increase significantly following unilateral whisker stimulation, a model of experience dependent plasticity. This increase is greatest between 2 and 8 h after the stimulus and is seen in both a synaptosomal fraction as well as a sub-cellular fraction enriched for polyribosomal complexes. In contrast, detectable levels of FMRP within the somatosensory cortex show either a decrease or no change after a kainic acid induced seizure compared to water treated controls. Our findings demonstrate that FMRP expression levels are modulated in vivo in response to neuronal activity and suggest a role for FMRP in activity dependent plasticity.

[1]  K. Mack,et al.  Induction of transcription factors in somatosensory cortex after tactile stimulation. , 1992, Brain research. Molecular brain research.

[2]  K. Mack,et al.  Multiple promoters direct stimulus and temporal specific expression of brain-derived neurotrophic factor in the somatosensory cortex. , 1998, Brain research. Molecular brain research.

[3]  R. Nussbaum,et al.  The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein , 1993, Cell.

[4]  P. Greengard,et al.  Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation , 1983, The Journal of cell biology.

[5]  Eric R Kandel,et al.  Restricted and Regulated Overexpression Reveals Calcineurin as a Key Component in the Transition from Short-Term to Long-Term Memory , 1998, Cell.

[6]  K. Mack,et al.  NGFI-C expression is affected by physiological stimulation and seizures in the somatosensory cortex. , 1995, Brain research. Molecular brain research.

[7]  D. Schlessinger,et al.  Fragile X genotype characterized by an unstable region of DNA , 1991, Science.

[8]  J. Serratosa,et al.  Decreased Expression of Calmodulin Kinase II and Calcineurin Messenger RNAs in the Mouse Hippocampus After Kainic Acid‐Induced Seizures , 1998, Journal of neurochemistry.

[9]  J. Yakel.  Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. , 1997, Trends in pharmacological sciences.

[10]  F. Tamanini,et al.  Different targets for the fragile X-related proteins revealed by their distinct nuclear localizations. , 1999, Human molecular genetics.

[11]  T. Webb,et al.  Prevalence of fragile X syndrome. , 1996, Journal of medical genetics.

[12]  J. Sutcliffe,et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome , 1991, Cell.

[13]  B. D. de Vries,et al.  The fragile X syndrome. , 1998, Journal of medical genetics.

[14]  R. Malenka,et al.  Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression , 1994, Nature.

[15]  I. Weiler,et al.  Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Mandel,et al.  The FMR–1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation , 1993, Nature Genetics.

[17]  S. Warren,et al.  FMR1 protein: conserved RNP family domains and selective RNA binding. , 1993, Science.

[18]  Guy Nagels,et al.  Fmr1 knockout mice: A model to study fragile X mental retardation , 1994, Cell.

[19]  S. Warren,et al.  The molecular basis of fragile X syndrome. , 1996, Cold Spring Harbor symposia on quantitative biology.

[20]  A T Hoogeveen,et al.  FMRP is associated to the ribosomes via RNA. , 1996, Human molecular genetics.

[21]  R. D'Hooge,et al.  Long-term potentiation in the hippocampus of fragile X knockout mice. , 1996, American journal of medical genetics.

[22]  I. Weiler,et al.  Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  P. Rutecki,et al.  The effects of seizures on the brain , 1996, Current opinion in neurology.

[24]  K. Wisniewski,et al.  The Fra(X) syndrome: neurological, electrophysiological, and neuropathological abnormalities. , 1991, American journal of medical genetics.

[25]  D. Absher,et al.  FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. , 1997, Molecular cell.

[26]  S. Warren,et al.  The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. , 1996, Human molecular genetics.

[27]  B. Oostra,et al.  Characterization and localization of the FMR-1 gene product associated with fragile X syndrome , 1993, Nature.

[28]  I. Weiler,et al.  Evidence for Altered Fragile-X Mental Retardation Protein Expression in Response to Behavioral Stimulation , 2000, Neurobiology of Learning and Memory.

[29]  E. Kandel,et al.  Genetic and Pharmacological Evidence for a Novel, Intermediate Phase of Long-Term Potentiation Suppressed by Calcineurin , 1998, Cell.

[30]  T. Herdegen,et al.  Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins , 1998, Brain Research Reviews.

[31]  S. Hersch,et al.  Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes , 1997, The Journal of Neuroscience.

[32]  S. Hendry,et al.  Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys , 1988, Neuron.

[33]  J. Mandel,et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome , 1991, Science.

[34]  W. Brown,et al.  Analysis of neocortex in three males with the fragile X syndrome. , 1991, American journal of medical genetics.