Autism and the serotonin transporter: the long and short of it

Abstract

Autism is a neurodevelopmental disorder manifesting early in childhood. Some symptoms of autism are alleviated by treatment with selective serotonin reuptake inhibitors, which are known to interact with the serotonin transporter. Moreover, variation in the gene that encodes the transporter (SLC6A4), especially the HTTLPR locus, is known to modulate its expression. It is natural, therefore, to evaluate whether this variation plays a role in liability to autism. We investigated the impact of alleles at HTTLPR and three other loci in SLC6A4 by using a large, independent family-based sample (390 families, 1528 individuals) from the NIH Collaborative Programs of Excellence in Autism (CPEA) network. Allele transmissions to individuals diagnosed with autism were biased only for HTTLPR, both for the narrow diagnosis of autism (P ¼ 0.035) and for the broader diagnosis of autism spectrum (P ¼ 0.007). The short allele of HTTLPR was significantly overtransmitted. Investigation of haplotype transmissions suggested that, in our data, biased transmission was only due to HTTLPR. With respect to this locus, there are now seven of 12 studies reporting significant transmission bias of HTTLPR alleles, a noteworthy result in itself. However, the studies with significant findings are almost equally divided between overtransmission of short and overtransmission of long alleles. We place our results within this extremely heterogeneous field of studies. Determining the factors influencing the relationship between autism phenotypes and HTTLPR variation, as well as other loci in SLC6A4, could be an important advance in our understanding of this complex disorder.

Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism

“…39 Serotonin levels are increased (red arrow) in a subset of autistic patients. 1,50 (c) Histopathological studies on post-mortem brain sections of patients with autism showed decreased overall measure of hippocampus and small, closely packed neurons. 37,38 Blue arrows indicate the neuronal signal circuitry pathway through the hippocampus via pyramidal neurons from the dentate gyrus to the CA3 and CA1 regions and finally back to the entorhinal cortex.…”

“…37 Association of 5-HTT with autism has been revealed in several but not all study groups worldwide. 19,49,50 In conclusion, it is intriguing that several rare cases of autism present with mutations in genes, all of which are hypothesized to modulate synaptic plasticity in the hippocampus. It remains to be elucidated if these and other genetic factors are contributing -via this or other pathways -to the development of aberrant neural central nervous system connections noticed in autism.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…The most common assessed variants are a deletion/ insertion polymorphism in the transcriptional control region of the SLC6A4 gene with functional effects (5HTTLPR) [227][228][229] and a variable number of tandem repeat in intron 2 (STin2). Several studies have found an association of the short alleles of 5HTTLPR with AD, 217,[230][231][232][233] fewer studies of the long alleles. 234,235 Some studies did not replicate these findings.…”

Modeling early cortical serotonergic deficits in autism

“…Pharmacotherapy with serotonergic agents that reduce CNS 5-HT generally worsen autistic symptoms [84] while those that increase available 5-HT via the high affinity 5-HT transporter (SERT) improve some autistic features [34]. Although somewhat variable, a number of recent reports indicate an association between variations in the gene that encodes SERT and a susceptibility to autism [33,43,112]. Whitaker-Azmitia and colleagues [66,123] propose a perinatal hyperserotonemic animal model for the pathophysiology of autism.…”