Autism spectrum disorders: possible implications of BDNF modulation through epigenetics

We read with interest the article by Abdallah et al. in which the authors reported decreased levels of the brain-derived neurotrophic factor (BDNF) in neonatal samples of children subsequently diagnosed with autism spectrum disorders (ASD). In addition, a down-regulation of neurotrophin-4 (NT-4) and transforming growth factor-β (TGF-β) was also noted [1].

BDNF and NT-4 are considered neurotrophins, i.e., proteins that modulate neuronal proliferation, migration, survival, and neuroplasticity through axonal and dendritic outgrowth. On the other hand, TGF-β is an immunosuppressive cytokine that plays an important role in the developmental fate throughout embryogenesis [2]. Several potential factors, from genetic to environmental, have been postulated as the main etiology of ASD. Moreover, the vast majority of these factors lead to disrupted synaptic pathways and abnormal formation of neuronal connections or elimination of those unsuitable [1].

BDNF, one of the most studied neurotrophic factors, was decreased in ASD [1]. In this regard, it has been reported the link between its abnormal synthesis and the pathophysiology of several neurological and psychiatric disorders such as Alzheimer′s, Parkinson′s, and Huntington diseases, bipolar disorder, major depressive disorder, schizophrenia or addiction. In addition, most of these pathologies are related with dysfunctional synapses development in the central nervous system [3]. Environmental factors during early, a critical period in brain plasticity, have subsequent long-term modifications in structural and functional aspects of brain activity. Thus, brain changes in early induced by adverse life conditions might be explained by epigenetic modifications. When it occurs in key genes, a mechanism exists wherein early experiences can have longlasting influences on gene expression, consequently affecting brain function and behavior. BDNF gene has been studied to relate early-life stress, brain responses, and behavioral outcome through neurodevelopment and plasticity. Aberrant BDNF gene mediates a molecular mechanism, whereby early-life adversity may produce stable modifications in brain and behavioral plasticity. Interestingly, it has been noted that adverse social interactions and environmental conditions during the first week of life can alter cortical BDNF gene expression through epigenetic mechanisms, specifically generating changes in BDNF-DNA methylation [3].

Based in the consensus of the ASD pathophysiology and in the widely demonstrated role of BDNF on the modulation of synaptic plasticity and its repair, the up-regulation of this neurotrophin during the gestation and neonate period could be an epigenetic factor to prevent or ameliorate the ASD grade. Promoting stimuli that increase brain levels of BDNF during the pre- and postnatal period, such as music and physical exercise, we can modulate the molecular mechanism through which synaptic plasticity could be restored. Although the music′s effectiveness on the ASD patients have been extensively investigated, the music stimulation during the gestation and early period increases the BDNF levels mediating the synaptic connections at the time of its main formation [4]. Moreover, benefits for neonates of controlled physical exercise during pregnant at metabolic and neurologic level have been reported. In fact, it has been shown that the improvements produced at cognitive level depend on the promotion of neurogenesis and synapses formation induced by BDNF [5].

For all above mentioned, it is inevitable to consider specific stimulation for the unborn, such as music and physical exercise, to modulate neurotrophic mechanisms, improving thus synapses formation, and therefore preventing abnormal process in ASD. Overall, restoring the dysfunctional neurodevelopment caused by BDNF through epigenetic mechanisms in the unborn, by means of music or exercise, could be crucial in the early period development of children.