Search

Serotoninergic dysfunction is highly implicated in autism. Serotonin transporter gene (SLC6A4) that regulates synaptic serotonin level has been investigated as a candidate gene for autism, but consensus opinion on possible association is still lacking. Converging evidences of platelet-hyperserotoninemia in approximately 25% of the patients, betterment of ritualistic behavior on administration of SSRI and linkage to chromosome 17q11 harboring SLC6A4, supports the hypothesis that SLC6A4 polymorphisms may contribute towards autism pathology. Our recent report on 5-HTTLPR marker represents the first study on genetic association of SLC6A4 with autism in the Indian population. Further analysis involving additional markers may reinforce the earlier hypothesis. So in the present study, we have investigated the association of a VNTR of 17 bp at intron2 (STin2) and an SNP at 3'UTR (HTT-3'UTR-SNP) of the gene with autism using family and population-based approaches. We have genotyped 421 individuals (93 autistic subjects, their parents and 160 controls) and consistent with other publications, family-based association studies using individual markers (STin2 and HTT-3'UTR-SNP) have not revealed any preferential allelic transmission to the probands. However, the interesting finding of strong linkage disequilibrium (LD) between the markers and significant disease-specific distortion in the distribution of HTT-3'UTR-SNP genotypes (T1chi(2)=5.19, P=0.02; OR=2.89, 95% CI=1.13-7.41) and the specific haplotypes of the two markers (LRS=11.85, p(c)=0.02), with higher frequencies of T/T genotype and 10-T haplotype in autistic cases suggests that either these markers or nearby markers of SLC6A4 that are in LD, may pose a risk towards autism in the Eastern Indian population.

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na+/Cl- dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy-Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case-control studies (chi2 = 1.314, P = 0.63) and family-based approaches (TDT chi2 = 0.22, P = 0.64 and HHRR-chi2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring (chi2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.

Tacrine is a potent and reversible inhibitor of acetylcholinesterase (AChE) in the brain. It produces tremor in animals, which is believed to be due to an increase in the brain acetylcholine level following AChE inhibition. The present study was undertaken to investigate the involvement, if any, of biogenic amines in the genesis of this motor dysfunction. Administration of tacrine (10-20 mg/kg, i.p.) produced dose- and time-dependent tremor in Balb/c mice. While in vivo inhibition of striatal AChE activity was observed only for the highest dose of tacrine, a dose-dependent increase in striatal choline acetyltransferase activity was obtained. Serotonin (5-HT) levels, as assayed following a sensitive HPLC-electrochemical procedure, were significantly increased in nucleus caudatus putamen, nucleus accumbens, substantia nigra, nucleus raphe dorsalis, olivary nucleus and the cerebellum. However, dopamine or norepinephrine levels remained unaltered in these areas of the brain. In animals treated with p-chlorophenylalanine, a specific tryptophan hydroxylase inhibitor and 5-HT depletor, tacrine failed to elevate the levels of 5-HT in the brain regions, and significantly attenuated tremor response to the drug. Tacrine-induced tremor was also significantly (83%) attenuated by 5-HT(2A/2C) receptor antagonist mianserin (5 mg/kg, i.p.), but methysergide (5 mg/kg, i.v.) could block tacrine-induced tremor only by 20%. Atropine (5 mg/kg, i.p.) antagonized tacrine-induced tremor by about 53%, but a combination of atropine and mianserin completely blocked the tremor response. These results indicate that the cholinergic tremor produced by tacrine in Balb/c mice is mediated via central serotonergic mechanisms, and stimulation of 5-HT(2A/2C) receptors plays a pivotal role in this motor dysfunction.