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Decreased mTOR Signaling Via p70S6K/eIF4B Is Associated with Loss of the Excitatory Postsynaptic Marker PSD-95 in Autism
Dendritic spines are small protrusions from dendrites where most excitatory synapses occur. Similar to other neural disorders including mental retardation, schizophrenia, fragile X and Rett syndromes, changes in spine number and shape lead to synaptic dysfunction and perturbed neuronal circuit development in autism. Local translation of dendritic mRNAs has been shown to play a pivotal role in spine morphogenesis and synaptic plasticity. Thus, we hypothesized that disruptions in dendritic mTOR-dependent translation initiation may contribute to spine pathology in the autistic brain. We previously found decreased components of the mTOR pathway in postmortem fusiform gyrus of subjects with autism compared to controls. mTOR influences protein translation at spines via two downstream effector pathways which are responsible for promoting translation of different pools of mRNAs. One cascade involves p70S6K and eukaryotic initiation factor 4B (eIF4B) and regulates translation of proteins belonging to the translation machinery such as elongation and initiation factors and ribosomal proteins, while the other comprises eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and eukaryotic initiation factor 4E (eIF4E) and controls translation of 5’ capped mRNAs coding for structural and functional synaptic proteins.
Objectives:
We aimed to examine which mTOR-mediated downstream signaling pathway is disrupted in autism and whether this disruption is associated with changes in PSD-95, a marker of excitatory synapses.
Methods:
Phospho-mTOR, mTOR, p70S6K, eIF4B, 4E-BP1, eIF4E and PSD-95 were measured by Western blotting in postmortem fusiform gyrus of 11 autism and 13 control subjects.
Results:
Significantly decreased phospho-mTOR, mTOR, p70S6K and eIF4B protein levels were observed in the fusiform gyrus of autism compared to control subjects. Surprisingly, no significant changes in 4E-BP1 and eIF4E protein expression were found in autism versus control fusiform gyrus, supporting the specificity of the p70S6K/eIF4B pathway deficit. Lastly, a significant reduction in PSD-95 protein was determined in autism subjects compared to controls.
Conclusions:
Decreased mTOR expression and activation were found in fusiform gyrus of autistic subjects compared to controls. Disruptions in mTOR downstream signaling pathways were specific to the p70S6K/eIF4B pathway, suggesting reduced translation of mRNAs mainly encoding components of the translational machinery. Remarkably, dysfunctional mTOR signaling was associated with a significant decrease in protein expression for the excitatory synaptic marker PSD-95, suggesting a reduction in excitatory synapses. In conclusion, reduced signaling via mTOR/p70S6K/eIF4B may result in decreased spine protein synthesis and thereby lead to loss of excitatory synapses. Reduced excitatory synapses in turn might perturb development and maintenance of functional cortical circuits and thus contribute to autism’s cognitive and behavioural deficits.