Usha Rajamma

Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-nitropropionic acid-induced rat model of Huntington's Disease.

Huntingtons disease (HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3‐nitropropionic acid (3‐NP)‐induced HD in rats where both drugs were administered simultaneously.

Sexual dimorphic effect in the genetic association of monoamine oxidase A (MAOA) markers with autism spectrum disorder

Autism spectrum disorders are heritable and behaviorally-defined neurodevelopmental disorders having skewed sex ratio. Serotonin as modulator of behavior and implication of serotonergic dysfunction in ASD etiology corroborates that serotonergic system genes are potential candidates for autism susceptibility. In the current study X-chromosomal gene, MAOA responsible for degradation of serotonin is investigated for possible association with ASD using population-based approach. Study covers analysis of 8 markers in 421 subjects including cases and ethnically-matched controls from West Bengal. MAOA marker, rs6323 and various haplotypes formed between the markers show significant association with the disorder. Stratification on the basis of sex reveals significant genetic effect of rs6323 with low activity T allele posing higher risk in males, but not in females. Haplotypic association results also show differential effect both in males and females. Contrasting linkage disequilibrium pattern between pair of markers involving rs6323 in male cases and controls further supports the sex-bias in genetic association. Bioinformatic analysis shows presence of Y-encoded SRY transcription factor binding sites in the neighborhood of rs1137070. C allele of rs1137070 causes deletion of GATA-2 binding site and GATA-2 is known to interact with SRY. This is the first study highlighting male-specific effect of rs6323 marker and its haplotypes in ASD etiology and it suggests sexual dimorphic effect of MAOA in this disorder. Overall results of this study identify MAOA as a possible ASD susceptibility locus and the differential genetic effect in males and females might contribute to the sex ratio differences and molecular pathology of the disorder.

Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders.

Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits.

Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population.

BACKGROUND Serotoninergic dysfunction leads to neurodevelopmental abnormalities and behavioral impairments. Platelet hyperserotoninemia is reported as the best identified endophenotype for autism spectrum disorders. Therefore, in the present study we investigate the association of TPH2, the rate limiting enzyme in 5-HT biosynthesis and ITGB3, a serotonin quantitative trait locus with ASD in the Indian population. METHODS Population and family-based genetic association and gene-gene interaction analyses were performed to evaluate the role of ITGB3 and TPH2 markers in ASD etiology. RESULTS Association tests using ITGB3 markers revealed significant paternal overtransmission of T allele of rs5918 to male probands. Interestingly for TPH2, we observed significant overrepresentation of A-A (rs11179000-rs4290270), G-A (rs4570625-rs4290270), G-G-A (rs4570625-rs11179001-rs4290270) and A-G-A (rs11179000-rs11179001-rs4290270) haplotypes in the controls and maternal preferential transmission of A-A (rs11179001-rs7305115), T-A-A (rs4570625-rs11179001-rs7305115) and T-A-A (rs11179000-rs11179001-rs7305115) and nontransmission of G-G-A (rs4570625-rs11179001-rs7305115) haplotypes to the affected offspring. Moreover, interaction of ITGB3 marker, rs15908 with TPH2 markers was found to be significant and influenced by the sex of the probands. Predicted individual risk, which varied from very mild to moderate, supports combined effect of these markers in ASD. CONCLUSION Overall results of the present study indicate likely involvement of ITGB3 and TPH2 in the pathophysiology of ASD in the Indian population.

Components of the folate metabolic pathway and ADHD core traits: an exploration in eastern Indian probands

We investigated role of the folate–homocysteine metabolic pathway in the etiology of attention-deficit hyperactivity disorder (ADHD) due to its importance in maintaining DNA integrity as well as neurotransmission. Functional gene variants in MTR (rs1805087), CBS (rs5742905), MTHFR (rs1801133 &rs1801131), MTHFD (rs2236225), RFC1 (rs1051266), plasma vitamin B12, folate and homocysteine were analyzed. rs1805087 ‘A’ showed strong association with ADHD. Vitamin B12 deficiency of ADHD probands (P=0.01) correlated with rs1801133 ‘T’ and rs1805087’GG’. Mild hyperhomocysteinemia (P=0.05) in the probands was associated with rs1805087 ‘AA’. Probands having rs1805087 ‘GG’ and rs1051266 ‘G’ was more inattentive. Hyperactivity–impulsivity score revealed association with rs5742905 ‘TT’ and rs2236225 ‘CC’, while rs1801133 ‘CC’ showed association with inattentiveness and hyperactivity–impulsivity. rs1801131 exhibited strong synergistic interaction with rs1051266 and rs2236225. This indicated that the folate–homocysteine pathway gene variants may affect ADHD etiology through mild hyperhomocysteinemia and vitamin B12 deficiency, factors known to be associated with cognitive deficit.

Monoamine oxidase B gene variants associated with attention deficit hyperactivity disorder in the Indo-Caucasoid population from West Bengal

BackgroundAttention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, excessive motor activity and impulsivity detected mostly during childhood. These traits are known to be controlled by monoamine neurotransmitters, chiefly dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA) and B (MAOB), two isoenzymes bound to the outer membrane of mitochondria, are involved in the degradation of monoamines and were explored for association with ADHD in different ethnic groups. In the present study, few exonic as well as intronic MAOB variants were analyzed in ADHD probands (N = 150) and ethnically matched controls (N = 150) recruited following the Diagnostic and Statistical Manual for Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioural attributes. Gene variants were analyzed by amplification of target sites followed by DNA sequencing and data obtained were analyzed by population based statistical methods.ResultsOut of 34 variants present in the analyzed sites, only seven functional variants, rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324 and rs3027440, were found to be polymorphic. rs2283728 ‘C’ (P = 3.45e-006) and rs3027440 ‘T’ (P = 0.02) alleles showed higher frequencies in ADHD probands as compared to controls. rs56220155 ‘A’ (P = 0.04) allele and ‘GA’ (P = 0.04) genotype showed higher frequencies in the male and female ADHD probands respectively as compared to sex-matched controls. Analysis of pairwise linkage disequilibrium revealed striking differences between probands and controls. Haplotype analysis revealed significantly higher occurrence of different haplotypes in the ADHD probands while some haplotypes were detected in the controls only. Higher scores for conduct problems were found to be associated with rs56220155 ‘A’ (P = 0.05) allele in the male ADHD probands. Multifactor dimensionality reduction analysis showed independent as well as interactive effects of polymorphic variants which were more robust in the male probands.ConclusionsSince all the polymorphic variants analyzed were functional, it may be inferred that MAOB gene variants are contributing to the etiology of ADHD in the Indo-Caucasoid population from eastern India which merits further in depth analysis.

An Association Analysis of Reelin Gene (RELN) Polymorphisms with Childhood Epilepsy in Eastern Indian Population from West Bengal

Epilepsy is a common neurological condition characterized by unprovoked seizure attacks. Early brain developmental abnormalities involving neuronal migration and lamination are implicated in childhood epilepsy. Reelin, a neuronal-signaling molecule plays a crucial role in these migratory processes. Therefore, reelin gene (RELN), which is located on human chromosome 7q22 is considered as a potential candidate gene for childhood epilepsy. In this study, we recruited 63 patients with childhood-onset epilepsy and 103 healthy controls from West Bengal in India. Genomic DNA isolated from leukocytes of cases and control individuals were used for genotyping analysis of 16 markers of RELN. Case–control analysis revealed significant over-representation of G/C and (G/C+C/C) genotypes, and C allele of exon 22 G/C marker (rs362691) in cases as compared to controls. Pair-wise linkage disequilibrium analysis demonstrated two separate LD blocks with moderately high D′ values in epileptic cases. Based on these data, we have carried out haplotype case–control analysis. Even though we found over-representation of A-C haplotype of intron 12 A/C/exon 22 G/C markers and haplotype combination involving G-allele of exon 22 marker in cases and controls, respectively, the overall test was not significant. LD in this region involving this marker was also more robust in epileptic cases. Taken together, the results provide possible evidences for association of exon 22 G/C marker or any marker in the vicinity, which is in LD with this marker with epilepsy in the West Bengal population. Further investigations involving higher sample sizes are warranted to validate the present finding.

Genetic variants of MAOB affect serotonin level and specific behavioral attributes to increase autism spectrum disorder (ASD) susceptibility in males

Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.

Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems

ABSTRACT An etiologically complex disorder, Attention Deficit Hyperactivity Disorder (ADHD), is often associated with various levels of cognitive deficit. Folate/vitamin B9 is crucial for numerous biochemical pathways including neural stem cell proliferation and differentiation, regulation of gene expression, neurotransmitter synthesis, myelin synthesis and repair, etc. and a scarcity has often been linked to cognitive deficit. Our pilot study in the field revealed significant association of few genetic variants with ADHD. Mild hyperhomocysteinemia and vitamin B12 deficiency was also noticed in the probands. In the present study additional genetic variants, folate and vitamin B6, which may affect folate‐homocysteine metabolic pathway, were investigated in 866 individuals including nuclear families with ADHD probands (N = 221) and ethnically matched controls (N = 286) to find out whether ADHD associated traits are affected by these factors. Population based analysis revealed significant over representation of MTRR rs1801394 “G” allele and “GG” genotype in all as well as male probands. Stratified analysis showed significantly higher frequency of RFC1 rs1051266 and BHMT rs3733890 “AG” genotypes in full term and prematurely delivered ADHD probands respectively. Probands with rs1801394 “GG” genotype and BHMT rs3733890 “G” allele showed association with hyperhomocysteinemia. MTHFR rs1801131, MTR rs1805087 and BHMT rs3733890 also showed association with ADHD index. While rs1051266, rs1801131, and rs1805087 showed association with behavioral problems, rs3733890 was associated with ODD score. Conduct problem exhibited association with RFC1 rs1051266, MTHFR rs1801133 and MTRR rs1801394. Gene‐gene interaction analysis revealed positive synergistic interactions between rs1051266, rs1801131 and rs1801394 in the probands as compared to the controls. It can be inferred from the data obtained that folate system genetic variants and mild hyperhomocysteimenia may affect ADHD associated traits by attenuating folate metabolism. HIGHLIGHTSFolate metabolic system gene variants and metabolite/co‐factor were analyzed for association with ADHD associated behavioral traits.MTRR rs1801394 “GG” allele showed significant association with ADHD and hyperhomocysteinemia.Mild hyperhomocystenemia of ADHD probands was also associated with BHMT rs3733890 “GG” genotype.This pilot study also showed association of the time of delivery with genetic variants of folate‐Hcy pathway.We infer that folate‐Hcy pathway genetic variants may affect Hcy level thus regulating ADHD associated behavioral problems.

Huntington’s disease: the coming of age

Huntington’s disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells. The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.