International Journal of Recent Biotechnology ISSN: 2322 – 0392 Available online at www.ijrbp.com Int. J. Rec. Biotech. 2014, 2 (1): 24-32 Research Article IJRB Gene - Hormone interactions: Biological and genetic implications in Mood disorders Kiran Kumar Halagur Bhoge Gowda1* Bangalore, India *Corresponding Author Email: [email protected] ABSTRACT There is now ample evidence of gender differences in basic neural processes and behaviors. Behaviors in mammals can be considered sexually dimorphic. It is proposed to be the end result of reciprocal influences between genes, and activational effects of neuroactive hormones and steroid receptors on the brain, learning, social and other environmental influences. Growing evidence suggests that this may, in part, reflect complex interactions between genomic and nongenomic actions of gonadal hormones and steroids at the cell and molecular level in the central nervous system (CNS). Neuroactive hormones (NAHs) and steroids (NASs) play a modulatory role in the CNS and affect many of the neurotransmitter systems thereby affecting neuronal excitability. Neuroactive hormones and steroids play an important role in the pathophysiology of psychiatric illness. The review highlights the gene-hormone interactions in the CNS, and the biological and genetic implications in mood disorders. Key words: CNS, Steroid, Hormone, Gene. INTRODUCTION Gender differences in Mood disorders Mood disorders exhibit familial transmission due to both genetic risk and environmental factors [1,2,3]. Familial transmission of mood disorders is demonstrated through various studies. Gender differences in the prevalence and incidence rates of mood disorders have been examined in various epidemiological, genetic and clinical studies [4]. Currier et al., [5] reported higher familial transmission rate of mood disorders for female probands than males. Fergusson et al., [6] found maternal mood disorder associated with mood disorder in daughters but not sons. Similarly, Baldassano et al., [7] reported higher rates of BPII in women and co-morbid thyroid disease and post-traumatic stress disorder as compared to men, in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center NIMH project. Female gender and recurrent major depression were more prevalent in the lowest quartile www.ijrbp.com episode frequency in families with at least three members with a major affective disorder [8]. Age of onset (AO) has been proposed as a promising criterion to select homogeneous subgroups for the genetic analysis of bipolar disorder. Grigoroiu-Serbanescu et al., [9] investigated the effect of the interaction between gender and family history (FH)-type on AO in bipolar disorder. Significant variation in AO according to the type of FH in females was observed but not in males. In the group with a FH of bipolar and/or schizoaffective disorder, females had an earlier AO than males. Literature review of epidemiological findings on sex differences in the prevalence of unipolar depression and putative risk factors [10], showed evidence for a female preponderance in unipolar depression, holding true across different cultural settings. Gender differences have been reported with reference to symptoms, prevalence and heritability of seasonal affective disorders (SAD). In the Seasonal Pattern Assessment Questionnaire (SPAQ) Women had about 1.5 24 Kiran Kumar, H.B. times higher prevalence than men [11]. In a large DEPRES Study dataset with population samples of six European countries the gender differences for major depression existed across all age groups [12]. Marcus et al., [13] reported a higher prevalence in women in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) in a multi center trial. Role of Neuroactive hormones and steroid receptors in the nervous system Neuroactive hormones and steroids exert their effect on neuronal function via genomic and nongenomic mechanisms (Fig-1,) reviewed in McEwen [15]; Rupprecht [14]. These Steroid receptors modulate transcription of various cellular genes, either positively or negatively; by interacting with specific hormone-response elements located in the target gene promoters/response elements (DNA sequences in the promoter region of a gene) after translocating to the nucleus. Int. J. Rec. Biotech. 2014, 2 (1): 24-32 Neuroactive hormones modulate serotonergic [15,16] and dopaminergic, neurons (Cookson) and cell surface ligand-gated ion channel receptors-GABAA and NMDA receptors [17]. They also modulate other neurotransmitter receptors, including nicotinic acetylcholine, AMPA, kainite, oxytocin, and glycine receptors (Rupprecht, 2003). Steroid hormones may also exert nongenomic actions through a variety of interactions with membrane receptors or secondary messenger cascades [18,19]. Studies have revealed that hormones and steroids affect transcription of a certain class of genes (McEwen, 1991) initiating a cascade of events that may have an impact on developmental and organizational effects on the brain. Cell and Molecular evidences of sexual dimorphism: Sexually dimorphic brain regions, such as the hypothalamus, appear to develop along gender Figure-1 www.ijrbp.com 25 Kiran Kumar, H.B. specific lines without the stimulus of gonadal hormones suggesting the role of other sexspecific genetic mechanisms [20]. Administration of nerve growth factor (NGF) antibodies to neonatal rats prevented testosterone-mediated defeminization of sexually dimorphic reproductive behavior and excitability of VMN-midbrain projections [21]. Similar results have been demonstrated with GAP43 a growth-associated protein – neuromodulin. Brain-derived neurotrophic factor (BDNF) is a key mediator of neuronal plasticity in the brain. A prospective study, demonstrated parameters such as age, gender and menstrual cycle had a specific impact on stored and circulating BDNF levels in peripheral blood, and platelets. A sexually dimorphic pattern of axonal outgrowth and synaptic connectivity in regions of the hypothalamus was observed [22, 23]. Based on these and other experimental evidences gender-specific hormone-induced structural changes in the VMN are presumed to underlie the expression of different genes. Animal model studies have shown that steroid hormones regulate the expression of inducible transcription factors. Dimorphic expression is demonstrated in the expression of AP-2 transcription factor in the bed nucleus of the stria terminalis and in the expression of Fos protein a product of the inducible transcription factor, Fos gene [24]. Estrogenic effects have been implicated in sexual differentiation of brain and behavior partly by affecting neuronal activity in the VMN hypothalamus [25]. A sex specific difference in the neuronal activity was observed in 17betaestradiol (E2, 10 nM) treated primary cultures of population of neurons of the VMN [26]. The frequency of spontaneous synaptic events, and amplitude differed between the sexes. Animal studies by LaPlant [27] suggest a hormonal mechanism of NFkappaB regulation that contributes to stress-induced depressive behaviors in female subjects and might represent Page No. xx-xx a mechanism for gender differences in prevalence rates of these disorders in humans. 2.2 Effects on gene expression Recent evidences using gene expression systems indicate that gonadal hormones and genes, by www.ijrbp.com Int. J. Rec. Biotech. 2014, 2 (1): 24-32 directly inducing sexually dimorphic patterns of neural development, could influence the sexual differences between male and female brains. Dewing et al [28] reported over 50 candidate genes, and confirmed seven genes, which show differential expression in the developing brains of male and female mice before any gonadal hormone influence. Similarly estrogen responsive genes have been reported using Low-density cDNA arraycoupled to PCR differential display [29]. Characterization of a set of clones showed that their expression in the adult female rat hypothalamus is sensitive to neonatal treatment with estrogen; and the increase in expression of mRNA level was before the initiation of puberty. Further,a study of Post-mortem human brain revealed a gender-specific gene expression pattern in neuronal subpopulations [30]. Neurochemical and Neurotransmitter Studies Gender influences in the post-mortem studies of human frontal cortex showed higher [3H] imipramine binding sites in females [31]. Some investigators have reported higher concentrations of serotonin reuptake sites in platelets of healthy women than in men [32, 33]. Gender differences in the postsynaptic serotonergic system is supported by positron emission tomography (PET) studies. Higher 5HT2 receptor binding capacity in men than in women in most brain regions especially in the frontal and cingulate cortices was observed. Gender differences in central 5-HT neurotransmission appear to depend partly on sex-related variation mechanisms [34]. Also, the 5-HT firing rate in dorsal raphe nucleus serotonergic neurons by ovarian hormones and steroids is modulated gender-dependently [35,36]. Also,Knockout studies of serotonin receptor genes, in animal models demonstrate gender differences in gene expression pattern and related behaviour [37]. Gender differences in GABA neurotransmission (McCarthy et al.), histaminergic neurotransmission [38] and dopamine neurotransmission [39] are also been established by KO studies. Taken together the results constitute strong evidence of sexual dimorphism in the brain and support the 26 Kiran Kumar, H.B. hypothesis that biological, neurochemical and neuroendocrinal mechanisms and alterations are sex dependent. Evidences from linkage and association studies Linkage studies Zubenko et al [40] reported a sex-specific susceptibility to unipolar Mood Disorders in families identified by probands with Recurrent, Early-Onset Major Depressive Disorder (REMDD), to a region on chromosome 2q33-34. The region harbors the CREB1 gene, which encodes a cAMP-responsive element-binding protein (CREB), a member of the bZIP family of transcription factors. The sex-specificity of the susceptibility locus identified in the study is hypothesized to be a result of synergistic interactions of CREB with nuclear estrogen receptors. Evaluation of the associated D2S2944 alleles using a case-control study design and subsequently using the transmission/disequilibrium test suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD [41]. Sex-specific genetic architecture of whole blood serotonin level (a sexually dimorphic trait) was assessed using the homozygosity-by-descent linkage method in Hutterites [42]. Although both males and females showed a high broad heritability, females had a higher additive component. Furthermore, the serotonin QTL on 17q, integrin beta 3 (ITGB3), and a novel locus on 2q influenced serotonin levels only in males, whereas linkage to a region on chromosome 6q was specific to females. Both sexes contributed to the linkage signals on 12q and 16p. Association studies Several gender specific associations in candidate genes have been reported in mood disorders, few association studies have been summarized here. GPR50 gene, an orphan G protein-coupled receptor (GPCR) was associated in female MDD group (Thomson et al., 2005). The -T50C Polymorphism in the GSK-3 Gene was association with Bipolar Disorder type II in women [43]. A haplotype (HP1) in the Disrupted in schizophrenia (DISC1) gene was www.ijrbp.com Int. J. Rec. Biotech. 2014, 2 (1): 24-32 overtransmitted to the female BPAD subjects, moreover, a significant decrease in DISC1 mRNA expression was observed in lymphoblasts from affected HP1 group compared to those from unaffected subjects [44]. Heterozygosity for the CREB1 gene promoter variant was associated with Mood Disorder among women and the Heterozygosity for the C deletion in intron 8 exhibited a protective effect against the development of Mood Disorders among women, but not men [45]. Association studies of some polymorphisms in the neurotransmitter genes also report gender specific associations. A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed in the female bipolar patients [46]. The -48A/G polymorphism of the DRD1 gene was associated with female bipolar subjects [47]. Similarly, the Ser23 allele of the 5-HT2C gene was over represented in female bipolar disorder subjects Polymorphisms in the GABRA1 and GABRA6 genes displayed significant associations with mood disorders in female patients [48]. In a pilot study testing the gender-specificity of the association between suicide attempts and serotonin transporter gene polymorphism (5HTTLPR), S individuals were significantly over represented in female attempters when compared with female controls and male attempters [49]. In another study healthy females with the s/s genotype at the 5HTTLPR polymorphism had higher 5-HIAA levels in the cerebrospinal fluid than males an index of serotonergic turnover. Evidences of Genotype-hormonal and clinical responses Glatz et al reported an allele-specific difference in the glucocorticosteroid-dependent increase in 5-HTT expression in immortalized human Blymphoblastoid cells. Functional reporter gene assays as well as 5-HT uptake and inhibitor binding measures revealed a genotypedependent (5HTTLPR “L”/”S”) response to glucocorticosteroid administration. In rhesus monkey, a 21-base pair (bp) insertion/deletion polymorphism analogous to the human serotonin transporter length variant (hSERT - 5HTTLPR), a sexually dichotomus 27 Kiran Kumar, H.B. interaction between promoter variation to the influence of adrenocorticotropic hormone (ACTH) response to stress was observed. Females, carrying the s allele, exhibited lower cortisol responses to stress (Barr et al., 2004). Allelic variation of 5-HTTLPR influenced the response to Serotonin selective re-uptake inhibitors (SSRIs) in female Panic Disorder subjects [50]. Furthermore, in platelets the effect of 5-HTTLPR genotype on long-term antidepressant drug exposure showed decreased SERT immunoreactivity in subjects homozygous for the short allele (SS), as compared to long allele (LL) [51]. Analysis of the functional HTR1A C-1019G polymorphism in the promoter region of HTR1A gene, female patients with -1019C/C genotype showed a better response to SSRI than -1019G carriers. An insertion/deletion (I/D) polymorphism within the Angiotensin converting enzyme (ACE) gene, is shown to determine ACE plasma concentration and is expressed in the CNS, where it degrades neuropeptides including substance P. Because of the possible antidepressant effects of SP antagonists, the influence of SP on both pathophysiology and mitigation of depression has been hypothesized. Female patients contributed significantly to the genotype dependent therapeutic outcome [52]. Recent findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options [53]. DISCUSSION A robust and growing body of evidences from epidemiological studies, animal model studies, and various human subject studies support the gender specific association in mood disorders and dimorphic pattern of brain functioning. Sex differences could result from parent-oforigin effects, linkage to sex chromosomes, genetic interaction, or from differences arising from sex-specific hormonal environments. The neural substrates underlying gender differences frequently involve the interaction of hormonal events with genes during development, adulthood, and environmental events. www.ijrbp.com Int. J. Rec. Biotech. 2014, 2 (1): 24-32 Differences in the transcriptional control of various proteins by gonadal hormones and steroids viz., neuropeptide levels, enzyme levels, and receptor subunit proteins, might be critical in determining gender-dependent behaviors. Hormonal interaction at the transcriptional or posttranslational level associations is demonstrated in intercaruncular bovine stromal cells [54] and in human osteoclasts [55]. 5HTT mRNA expression in serotonergic neurons was reduced by estrogen in Rhesus macaques [56] suggesting a trans effect of hormones on the loci in females. The effects of gender on the regulation of many physiological traits are well documented. Linkage of other complex traits like the gonadal fat mass [57], Bone mineral density (BMD) [58]. Genetic factors underlying manifestation of disease, physiology, disease and drug response appear to differ between male and female patients. 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