The molecular mechanism and behavioral abnormality in autism models

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Dendritic filopodia are most abundant during periods of rapid synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal spine formation may underlie learning and memory function, and abnormal spine formation may be associated with the pathogenesis of mental retardation and/or autism.Mutation of tuberous sclerosis complex (TSC)-2 causes a hereditary autistic disorder in tuberous sclerosis. TSC2 has GAP activity towards small GTPase rheb, and TSC2 antagonizes mTOR pathway by stimulation of GTP hydrolysis of rheb. We analyzed Eker rats heterozygous for a mutation in the tsc2 to examine an involvement of TSC pathway in synaptogenesis. TSC2 mutation caused an inhibition of spine formation in cultured hippocampal neurons. A similar abnormality in spine formation was also observed in wild-type neuron expressed with a GTP-bound form of rheb. Thus, the excessive activation of rheb may cause the disturbance of the dendritic spinogenesis. We next attenuated such excessive activity of rheb-mTOR pathway with an mTOR inhibitor rapamycin. Rapamycin suppressed a phosphorylation of mTOR-downstream p70 S6 kinase, but did not increase the spine formation in tsc2-disrupted neurons, indicating that mTOR pathway may not be involved in spinogenesis. To identify another downstream target of rheb, we performed yeast two-hybrid screening and found a rheb-binding protein (RBP). Knockdown of RBP induced the spine formation in tsc2-mutated neurons. Conversely, overexpression of RBP abolished the maturation to spines in wild-type neurons. Furthermore, the expression of dominant-negative rheb reduced the amount of RBP, and increased dendritic spinogenesis in tsc2-mutated neurons. These results suggest that TSC2 may regulate the dendritic spine formation by controling neuronal RBP amount in a rheb-dependent manner.