Decreased Akt and Changes in Relative Levels of TrkB Isoforms in Autism

Background: Defects in synaptic development and plasticity are thought to lead to autism. Since brain-derived neurotrophic factor (BDNF) plays a crucial role in synaptogenesis and synaptic plasticity in the developing and mature brain, altered BDNF signaling could contribute to the pathogenesis of autism. We have previously found increased BDNF levels in post-mortem brain tissue of subjects with autism compared to controls, as measured by ELISA, and a genetic association between the high-affinity BDNF receptor, TrkB, and autism has been reported. TrkB is expressed in three splice variants. Full-length receptors (TrkB-FL) contain an intracellular catalytic tyrosine kinase domain and mediate classic neurotrophic BDNF signaling. Conversely, the two truncated TrkB isoforms are able to bind and sequester BDNF but, lacking tyrosine kinase activity, cannot elicit the normal cellular response to BDNF. We hypothesize that altered relative levels of TrkB receptor isoforms may contribute to deficits in BDNF signaling which account for aberrant neuronal function in autism. BDNF is believed to regulate dendritic development through TrkB activation of the PI3K-Akt-mTOR signaling pathway. We propose that dysregulation of the pathway may occur at different levels including ligand, receptors, and downstream signaling cascade effectors.

Objectives:  To investigate whether or not the BDNF/TrkB signaling pathway is disrupted in autism by comparing protein expression of TrkB isoforms and Akt in cortical tissue of autism versus control subjects.

Methods:  We measured protein expression of TrkB isoforms by Western blotting in post-mortem fusiform gyrus tissue of autism (n=11) and control subjects (n=13), and determined TrkB-FL and truncated TrkB isoform ratios. As a downstream effector of the BDNF/TrkB pathway, we next examined total Akt protein expression by Western blotting in the same cohort.

Results:  We found significantly increased truncated TrkB isoforms, significantly reduced TrkB-FL and a highly significant reduction of the TrkB-FL/truncated TrkB protein ratio in autism subjects compared to controls. Akt protein levels were also significantly decreased in autism compared to control tissue.

Conclusions:  Decreased TrkB-FL and Akt levels in autism suggest downregulation of the BDNF/TrkB signaling pathway. In addition, increased truncated TrkB isoforms may abnormally sequester the high levels of BDNF seen in autism. These findings point to an impaired cellular response to BDNF in autism. Moreover, a dysfunctional PI3K-Akt-mTOR pathway activated by BDNF through TrkB receptors may contribute to changes in dendritic development, thereby affecting communication at synapses. Aberrant cellular response to BDNF may lead to defects in synaptic development and plasticity which could account for the behavioral deficits typical of autistic disorder.