Dysfunctional BDNF/TrkB/PI3K Signaling in Autism Disrupts Intracellular Pathways Regulating Spine Protein Synthesis and Dynamics

Background:  Impairments in cortical connectivity are a hallmark of autism and account for cognitive and behavioural deficits of autistic patients. Both aberrant spine protein synthesis and disrupted remodeling of actin cytoskeleton may affect spine formation, stabilization, size and density, thereby resulting in synaptic dysfunction and perturbed neuronal circuit development. Local protein synthesis and actin reorganization at synapses are regulated by intracellular signaling cascades triggered by BDNF/TrkB-mediated activation of PI3K. We previously demonstrated imbalances in BDNF and TrkB isoforms and decreased Akt protein in postmortem brain tissue of subjects with autism compared to controls.

Objectives:  To investigate whether BDNF/TrkB-activated intracellular cascades, PI3K-Akt-mTOR, involved in spine protein synthesis, and PI3K-Eps8-Rac, regulating synapse formation, are disrupted in autism.

Methods: We examined p70S6K, an mTOR downstream effector which can be taken as a measure of altered mTOR-mediated protein synthesis, and Eps8, a signaling protein that is part of a trimeric complex which links BDNF-mediated PI3K activation to Rac-induced remodeling of actin cytoskeleton at synapses. We also assayed protein expression of Erk1/2, a signaling molecule activated by BDNF/TrkB, the synaptosomal protein SNAP-25 and the pan-neurotrophin receptor p75NTR which signals through the Rac-Rho pathway. Protein was examined by Western blotting in postmortem fusiform gyrus of autism and control subjects. 

Results:  Significantly decreased p70S6K and Eps8 protein levels were found in fusiform gyrus of subjects with autism compared to controls. No significant difference in Erk1/2 or SNAP-25 protein expression was measured in autism compared to control tissue. Lastly, a trend towards increased p75 receptor was observed in autism subjects compared to controls.

Conclusions:  Both reduced p70S6K and Eps8 protein levels are consistent with the down-regulation of the BDNF/TrkB signaling pathway that we previously demonstrated in fusiform gyrus of autistic subjects compared to controls. This suggests disruption of spine protein translation through p70S6K and remodeling of the actin cytoskeleton through Eps8 at synapses. Dysregulation of spine dynamics and densities is further supported by the trend towards elevated p75 receptor in autism which is consistent with increased proBDNF protein we observed in autism compared to control tissue, and likely affects regulation of spine dynamics and density via Rac/Rho. Since changes in spine protein translation, dynamics and stability due to dysfunctional BDNF/TrkB/p75 signaling may alter cortical connectivity, the balance between excitatory and inhibitory currents, and synaptic plasticity and function, abnormalities at spines may be the underlying biological mechanism responsible for autism core symptoms.