Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome.
Fragile X syndrome (FXS) has so far resisted efforts to define the basic cellular defects caused by the absence of a single protein, fragile X mental retardation protein (FMRP), because the patients have a wide variety of symptoms of varying severity. Immature-appearing dendritic spines on neurons found in FXS patients and fmr1-KO mice suggest a role for FMRP in modulating production of synaptic structural proteins. We isolated cortical synaptoneurosomes from WT and KO mice and studied MAPK pathway activation after group I metabotropic glutamate receptor (mGluR) stimulation. Here, we show that ERK in KO synaptoneurosomes is rapidly dephosphorylated upon mGluR1/5 stimulation, whereas it is phosphorylated in WT mice, suggesting that aberrant activation of phosphatases occurs in KO synapses in response to synaptic stimulation. In KO synapses, protein phosphatase 2A (PP2A) is overactivated after mGluR1 stimulation, and tyrosine phosphatase is overactivated after mGluR5 stimulation, causing the rapid deactivation of ERK. ERK activation can be restored in KO by pretreatment with phosphatase blockers; blocking of PP2A by okadaic acid could successfully restore normal ERK activation in KO synaptoneurosomes. We propose that overactivation of phosphatases in synapses may be a key deficit in FXS, which affects synaptic translation, transcription, and synaptic receptor regulation.
Kim
Soong Ho
SH
Beckman Institute, Neuroscience Program, and Departments of Psychology, Psychiatry, and Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Markham
Julie A
JA
Weiler
Ivan Jeanne
IJ
Greenough
William T
WT
D000818:Animals; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013997:Time Factors
D048049:Extracellular Signal-Regulated MAP Kinases; D051860:Fragile X Messenger Ribonucleoprotein 1; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse