Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.
The abnormal spine morphology found in fragile X syndrome (FXS) is suggestive of an error in the signaling cascades that organize the actin cytoskeleton. We report here that physiological activation of the small GTPase Rac1 and its effector p-21 activated kinase (PAK), two enzymes critically involved in actin management and functional synaptic plasticity, is impaired at hippocampal synapses in the Fmr1-knock-out (KO) mouse model of FXS. Theta burst afferent stimulation (TBS) caused a marked increase in the number of synapses associated with phosphorylated PAK in adult hippocampal slices from wild-type, but not Fmr1-KO, mice. Stimulation-induced activation of synaptic Rac1 was also absent in the mutants. The polymerization of spine actin that occurs immediately after theta stimulation appeared normal in mutant slices but the newly formed polymers did not properly stabilize, as evidenced by a prolonged vulnerability to a toxin (latrunculin) that disrupts dynamic actin filaments. Latrunculin also reversed long-term potentiation when applied at 10 min post-TBS, a time point at which the potentiation effect is resistant to interference in wild-type slices. We propose that a Rac>PAK signaling pathway needed for rapid stabilization of activity-induced actin filaments, and thus for normal spine morphology and lasting synaptic changes, is defective in FXS.
Chen
Lulu Y
LY
Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697, USA.
Rex
Christopher S
CS
Babayan
Alex H
AH
Kramár
Eniko A
EA
Lynch
Gary
G
Gall
Christine M
CM
Lauterborn
Julie C
JC
D000199:Actins / Q000378:metabolism; D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009479:Neuropeptides / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D000199:Actins; D051860:Fragile X Messenger Ribonucleoprotein 1; D009479:Neuropeptides; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C497684:Fmr1 protein, mouse; C484602:Rac1 protein, mouse