Fernando López-Armenta

Autism Spectrum Disorders (ASD) comprise a group of heterogeneous and complex neurodevelopmental disorders. Genetic and environmental factors contribute to ASD etiology. DNA methylation is particularly relevant for ASD due to its mediating role in the complex interaction between genotype and environment and has been implicated in ASD pathophysiology. The lack of diversity in DNA methylation studies in ASD individuals is remarkable. Since genetic and environmental factors are likely to vary across populations, the study of underrepresented populations is necessary to understand the molecular alterations involved in ASD and the risk factors underlying these changes. This study explored genome-wide differences in DNA methylation patterns in buccal epithelium cells between Mexican ASD patients (n = 27) and age-matched typically developing (TD: n = 15) children. DNA methylation profiles were evaluated with the Illumina 450k array. We evaluated the interaction between sex and ASD and found a differentially methylated region (DMR) over the 5′UTR region of ZFP57 and one of its targets, RASGRF2. These results match previous findings in brain tissue, which may indicate that ZFP57 could be used as a proxy for DNA methylation in different tissues. This is the first study performed in a Mexican, and subsequently, Latin American, population that evaluates DNA methylation in ASD patients.

Introduction. The study of autistic spectrum disorders (ASD) at the genetic level is extremely important to understand their origin. In Mexico, there are few works addressed from this perspective. Objective. We investigated the role of the Brain Derived Neurotrophic Factor ( BDNF ) gene variant rs6265 G/A for single nucleotide polymorphism analysis in Mexican children with ASD using a case-control association design. Method. We made a pilot study by case-control analysis adjusting by gender, age, and ancestry. Results. Our study found no association between the BDNF rs6265 gene polymorphism and ASD [ p = .419, OR = 1.597 (.514, 4.967)]. Discussion and conclusion. Worldwide, the results of case-control association studies with the rs6265 of BDNF are controversial and do not always replicate. This may be due to the ethnicity of our population and additional factors not studied in the present work. Our study suggests that the SNP rs6265 is not contributing for ASD susceptibility in Mexican population.

Cannabinoid CB1 receptors (CB₁R) and serotonergic 2A receptors (5HT_2AR) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB₁R-5HT_2AR heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na⁺ currents in patch clamp recordings. Interestingly, CB₁R-5HT_2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB₁R-5HT_2AR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.