BDNF-Akt-Bcl2 Anti-Apoptotic Signaling Pathway Is Compromised in the Brain of Autistic Children

Background: It has been reported that many areas of the brain in autistic individuals show abnormalities including loss of pyramidal neurons and granule cells in the hippocampus, as well as significant loss and atrophy of Purkinje cells in the cerebellum.      However, there is a paucity of neurochemical data paralleling these neurohistologic findings in the autistic brain. Emerging evidence points to apoptotic mechanisms being involved in certain neuropsychiatric disorders, including autism. However it is not known whether apoptosis is deregulated in the brain of autistic individuals.  

Objectives: The aim of this study is to determine the roles of apoptotic gene p53 and anti-apoptotic gene Bcl2 in the autistic brain, as well as how the apoptosis related genes are regulated.

Methods: Frozen human brain tissue (frontal cerebral cortex) of 6 autistic patients and 6 age matched control subjects were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders. Donors with autism fit the diagnostic criteria of the Diagnostic and Statistical Manual-IV, as confirmed by the Autism Diagnostic Interview-Revised. Participants were excluded from the study if they had a diagnosis of fragile X syndrome, epileptic seizures, obsessive–compulsive disorder, affective disorders, or any additional psychiatric or neurological diagnoses.  This study was approved by the Institutional Review Board of the NY State Institute of Basic Research. In this study, Western Blot Analyses were used to detect the expression levels of Bcl2, Akt and Phospho-Akt (T308) in the brain homogenates. Immunohistochemistry studies were used to examine the expression of p53 in the brain sections.  Enzyme-Linked Immuno Sorbent Assay (Elisa) was used to determine the concentration of brain-derived neurotrophic factor (BDNF) in the brain homogenates.

Results: Our studies show that Bcl2 is significantly down regulated, while the expression of p53 is increased in the brain of autistic children in comparison with age matched controls. We also found that the expression and phosphorylation/activation of Akt kinase that regulates Bcl2 are significantly decreased in the autistic brain. The down-regulation of Akt may result from decreased concentration of BDNF, the growth factor that modulates Akt activities

Conclusions: These results suggest that apoptosis may play an important role in the pathogenesis of autism and the compromised BDNF-Akt-Bcl2 anti-apoptotic signaling pathway could be one of the underlying mechanisms responsible for the pathological changes in the autistic brain.