Dataset Information

Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.

ABSTRACT: 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.

SUBMITTER: Chen LY

PROVIDER: S-EPMC2929244 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.

Chen Lulu Y LY Rex Christopher S CS Babayan Alex H AH Kramár Eniko A EA Lynch Gary G Gall Christine M CM Lauterborn Julie C JC

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100801 33

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 incr ...[more]

PMID: 20720104

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Project description:Key pointsMuscle-specific genetic ablation of p21-activated kinase (PAK)2, but not whole-body PAK1 knockout, impairs glucose tolerance in mice. Insulin-stimulated glucose uptake partly relies on PAK2 in glycolytic extensor digitorum longus muscle By contrast to previous reports, PAK1 is dispensable for insulin-stimulated glucose uptake in mouse muscle.AbstractThe group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 are activated in response to insulin in skeletal muscle and PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle. Interestingly, PAK1 has been suggested to be required for insulin-stimulated glucose transporter 4 translocation in mouse skeletal muscle. Therefore, the present study aimed to examine the role of PAK1 in insulin-stimulated muscle glucose uptake. The pharmacological inhibitor of group I PAKs, IPA-3 partially reduced (-20%) insulin-stimulated glucose uptake in isolated mouse soleus muscle (P < 0.001). However, because there was no phenotype with genetic ablation of PAK1 alone, consequently, the relative requirement for PAK1 and PAK2 in whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake was investigated. Whole-body respiratory exchange ratio was largely unaffected in whole-body PAK1 knockout (KO), muscle-specific PAK2 KO and in mice with combined whole-body PAK1 KO and muscle-specific PAK2 KO. By contrast, glucose tolerance was mildly impaired in mice lacking PAK2 specifically in muscle, but not PAK1 KO mice. Moreover, while PAK1 KO muscles displayed normal insulin-stimulated glucose uptake in vivo and in isolated muscle, insulin-stimulated glucose uptake was slightly reduced in isolated glycolytic extensor digitorum longus muscle lacking PAK2 alone (-18%) or in combination with PAK1 KO (-12%) (P < 0.05). In conclusion, glucose tolerance and insulin-stimulated glucose uptake partly rely on PAK2 in glycolytic mouse muscle, whereas PAK1 is dispensable for whole-body glucose homeostasis and insulin-stimulated muscle glucose uptake.

Dataset Information

Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.

Publications

Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome.

Similar Datasets

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