Friday, May 8, 2009
Northwest Hall (Chicago Hilton)
Background: Autism is a neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors, detectable in early childhood. The serotonergic system, which has an enormous influence over several brain functions, including memory, learning, mood, and behavior, has been suggested to be developmentally dysregulated in autism. Altered developmental dynamics of serotonin synthesis and elevated whole blood serotonin have been observed in autism. Serotonin is involved in various aspects of neurodevelopment that might influence anxiety-like and aggressive behaviors. Extracellular serotonin concentration is regulated by the serotonin transporter (SERT), which mediates the presynaptic reuptake of serotonin, on termination of neurotransmission. SERT is the major target of selective serotonin reuptake inhibitors, which are used in the treatment of functional impairments associated with autism. A single-photon emission computed tomography (SPECT) study reported reduced SERT binding capacity in several brain regions of autistic children compared to controls. SERT expression, and the factors that regulate the expression of SERT, might thus have a crucial role in the pathogenesis of autism.
Objectives: We carried out mRNA expression analyses and genetic association studies of the following genes that have been reported to influence the expression of SERT, (i) syntaxin 1A (STX1A); (ii) roundabout, axon guidance receptor, homolog 3 (ROBO3); (iii) integrin, beta 3 (ITGB3); (iv) myristoylated alanine-rich protein kinase C substrate like protein (MacMARCKS).
Methods: Differential expression of mRNA between control and autism samples was examined in the following postmortem brain samples obtained from Autism Tissue Project (ATP), (i) anterior cingulate (AC) (13 control, 8 autism); (ii) motor cortex (MC) (8 control, 7 autism); (iii) thalamus (9 control, 8 autism). Quantitative real-time PCR (qRT-PCR) analysis was done by TaqMan method; the fold change in gene expression between the control and autism groups was determined by calculating 2-DDCT. Family-based genetic association studies were carried out in samples of two different ethnic origins, (i) 252 Caucasian trio samples obtained from Autism Genetic Resource Exchange (AGRE); (ii) 126 Japanese trio samples. TaqMan method was used to score SNPs, and markers were tested for association by transmission disequilibrium test (TDT).
Results: We observed altered expressions of genes in the various brain regions of autism patients as following, (i) STX1A: decreased expression in the AC of autism patients (p=0.008); (ii) ROBO3: elevated expression in the AC (p=0.028) and in the MC (p=0.038) of autism patients; (iii) ITGB3: elevated expression in the AC (p=0.003) and in the thalamus (p=0.039) of autism patients; (iv) MacMARCKS: elevated expression in the AC of autism patients (p=0.004). We also found (i) SNP and haplotype associations of STX1A with autism in Caucasian and Japanese samples (ii) SNP and haplotype associations of ROBO3 with autism in Caucasian samples. Further, STX1A showed association with ADI-R_D (early developmental abnormalities) and ROBO3 showed association with ADI-R_A (social interaction) scores.
Conclusions: Several of the genes related to the serotonergic system showed altered expressions in various brain regions of autism patients compared to controls. We suggest a possible role of these genes in the pathogenesis of autism through regulation of serotonergic system.