Association of 5-HT1B receptor gene and antisocial behavior in alcoholism

Summary. The 5-HT1B receptor gene has been postulated to play a modulatory role in alcohol consumption and alcohol dependence, and was considered a candidate gene for alcoholism. More recently, the association of the 5-HT receptor gene polymorphism and antisocial personality traits in alcoholism has been discussed. This possible association was studied using material from our gene bank for alcoholism. The research instruments used to phenotype patients were partly adopted from the US Collaborative Study on the Genetics of Alcoholism (COGA) which include anxiety- and depression-related scales from personality inventories such as the temperament and character inventory (TCI), the NEO-Five-Factor Inventory (NEO-FFI) and the Minnesota Multiphase Personality Inventory (MMPI-2). Based on the examination of 164 alcoholic subjects, an association was found between a lower frequency of the 5-HT 1B 861C allele, antisocial personality traits and conduct disorder in alcohol-dependent subjects. Adult antisocial personality occurred more often in males than females. Possible implications of these findings are discussed.     

Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts.

BACKGROUND: In the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior. METHODS: After a one-year follow-up study of 103 patients hospitalized after a suicide attempt, patients have been genotyped for both the A218C TPH and the functional S/L 5-HTTLPR polymorphisms. RESULTS: Patients who reattempted suicide during the follow-up period had significantly higher frequencies of the S allele and the SS genotype. The odds ratio for the SS genotype vs. the LL genotype was 6.5 (95% CI [1.18-35.84]). No difference was observed for TPH gene. Patients carrying the SS genotype were more impulsive. However, multivariate analysis suggested an independent effect of both the SS genotype and impulsivity on the risk of repeated suicide attempts. CONCLUSIONS: These results suggest that the 5-HTTLPR SS genotype is associated with further suicide attempts among patients who have previously attempted suicide.     

Genetic and environemental factors in conduct problems and adult antisocial behavior among adult female twins

Most twin and adoption studies of conduct problems have demonstrated modest genetic effects but substantial contributions of shared family environment. Conversely, most investigations have shown marked genetic influences but modest contributions of shared family environment in adult antisocial behavior. However, most previous work has focused on male subjects. We obtained retrospective reports of DSM-III-R-defined conduct disorder (CD) and adult antisocial behaviors from a population-based sample of female-female twin pairs. Genetic and environmental contributions to conduct problems and adult antisocial behaviors were examined using polychoric correlation coefficients and univariate structural equation modeling. Statistically significant but modest heritability was observed for conduct problems. A small, statistically nonsignificant contribution of shared family environment to CD behavior was also noted. Adult antisocial symptoms showed modest contributions of both additive genetic and shared family environmental factors. In both childhood and adulthood, the largest influence on antisocial behavior was individual-specific environment. Our findings support the importance of both genetic and environmental factors in antisocial behavior among women as well as the possibility that the relative importance of each set of influences differs by sex in both childhood and adulthood.     

Morphological and gene expression similarities suggest that the ascidian neural gland may be osmoregulatory and homologous to vertebrate peri-ventricular organs

Summary The central nervous system (cerebral ganglion) of adult ascidians is linked to the neural gland complex (NGC), which consists of a dorsal tubercle, a ciliated duct and a neural gland. The function of the NGC has been the subject of much debate. The recent publication of the complete genomic sequence of Ciona intestinalis provides new opportunities to examine the presence and distribution of protein families in this basal chordate. We focus here on the ascidian neuropeptide G-protein-coupled receptors (GPCRs), the vertebrate homologues of which are involved in homeostasis. In situ hybridization revealed that five Ciona GPCRs [vasopressin receptor, somatostatin receptor, CRH (corticotropin-releasing hormone) receptor, angiotensin receptor and tachykinin receptor] are expressed in the NGC of adult ascidians. These findings, together with histological and ultrastructural data, provide evidence to support a role for the ascidian NGC in maintaining ionic homeostasis. We further speculate about the potential similarities between the ascidian NGC and the vertebrate choroid plexus, a neural peri-ventricular organ.     

Psychophysiological responses in ADHD boys with and without conduct disorder: implications for adult antisocial behavior

OBJECTIVE: Several studies have demonstrated that the presence of attention-deficit/hyperactivity disorder (ADHD) in childhood increases the risk of antisocial behavior developing in adulthood. However, because previous research did not consider comorbid conduct disorder (CD), the question of whether ADHD by itself or only the association of ADHD with CD implies a risk of adult antisocial behavior developing is still under discussion. METHOD: Because several characteristics of psychophysiological response had been shown to be associated with future increased likelihood of adult antisocial behavior, autonomic arousal as well as electrodermal responses to orienting and aversive stimuli were assessed in 26 boys with ADHD+CD compared with 21 boys with ADHD alone and 21 controls. RESULTS: Boys with a comorbid condition of ADHD+CD showed a decrement of autonomic responses and a more rapid habituation to orienting and aversive startling stimuli compared with age-matched children with ADHD alone. CONCLUSIONS: Boys with ADHD+CD show a psychophysiological response pattern that is very similar to that reported in antisocial personalities. These findings give further support for a high persistence of antisocial behavior from childhood to adulthood, while no evidence was found that ADHD itself is associated with a predisposition to antisocial behavior.     

HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes

Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501-restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.     

No association between the HTR1A gene and suicidal behavior: a meta-analysis

ObjectiveDysfunction of serotonin 1A receptors (HTR1A) may play a role in the genesis of suicidal behavior. We studied the association between a functional polymorphism in the HTR1A gene and suicidal behavior.MethodWe performed a meta-analysis of published genetic association studies by searching through Medline, PubMed, and Web of Science databases to analyze a possible correlation between the rs6295 polymorphism and suicidal behavior in different populations.ResultsFour studies comprising a total of nine hundred and fifty seven patients with suicidal behavior and nine hundred and fifty seven controls were the eligible. The G allele of the rs6295 polymorphism may not be associated with suicidal behavior (Random-effects model: OR = 1.08; 95% CI: 0.80–1.45; p(Z) = 0.80) in presence of heterogeneity (Q = 17.84, df = 4, p = 0.0013). In a second analysis that presented no heterogeneity, a negative association was also observed (OR = 0.94; 95%CI: 0.79–1.13; p(Z) = 0.99).ConclusionTo our knowledge, the present study is the first meta-analysis searching for a correlation between rs6295 of HTR1A and suicidal behavior. Our results showed no association between HTR1A and suicidal behavior. However, more studies assessing different populations, as well as larger samples, are needed.     

Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation

BRCA-1 is a tumor suppressor gene that plays a role in DNA repair and cellular growth control. Here we show that BRCA-1 mRNA is expressed by embryonic rat brain and is localized to the neuroepithelium containing neuronal precursor cells. The expression of BRCA-1 decreases during rat brain development, but BRCA-1 is expressed postnatally by proliferating neuronal precursor cells in the developing cerebellum. Neural stem cells (NSC) prepared from embryonic rat brain and cultured in the presence of epidermal growth factor were positive for BRCA-1. Induction of NSC differentiation resulted in down-regulation of BRCA-1 expression as shown by RNA and protein analyses. In addition to embryonic cells, BRCA-1 is also present in NSC prepared from adult rat brain. In adult rats, BRCA1 was expressed by cells in the walls of brain ventricles and in choroid plexus. The results show that BRCA-1 is present in embryonic and adult rat NSC and that the expression is linked to NSC proliferation.     

Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder

CONTEXT: Early-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene. OBJECTIVE: To test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction. DESIGN, SETTING, AND PARTICIPANTS: A family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ.Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview. RESULTS: The results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006). CONCLUSIONS: Early-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.     

Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes

P-glycoprotein (P-gp, ABCB1) and the multidrug resistance-associated protein 1 (Mrp1, ABCC1) are two ATP-driven pumps that mediate the export of organic anions from cells and may confer cellular resistance to many cytotoxic hydrophobic drugs. Immunohistochemistry has shown that P-gp is expressed in rat brain capillary vessels forming the blood-brain barrier (BBB). Mrp1 mRNAs have been detected by RT-PCR in rat brain isolated capillaries. Although many studies have been published in this field, very little information is available on the expression, distribution and physiological functions of the two pumps in rat brain. To characterize the cerebral expression of both P-gp and Mrp1 transporters, we studied immunoreactions of rat brain sections with the two most commonly used antibodies: the monoclonal C219 (anti-P-gp) and the polyclonal 6KQ (anti-Mrp1). Immunological analyses revealed heterogeneity of the P-gp and Mrp1 expressions in rat brain. Indeed, choroidal and ependymal cells expressed Mrp1 rather than P-gp. However, tanycytes lining the third ventricle were strongly immunoreactive with both antibodies, suggesting a particular role for these cells in drug efflux mechanisms. Because of the detection of a 70-kDa component with 6KQ antibodies, immunoreactions obtained in rats were compared with these obtained in wild type and mrp1(-/-) mice. It showed that a positive reaction at the apical surface of the ependymal layer remained obvious, showing that 6KQ antibodies recognize an ependymal molecule, differing from the Mrp1. In addition, a continuous expression of C219-labeled epitopes, similar to endothelial labeling, was detected at the blood-brain barrier, whereas a discontinuous labeling, co-localized with glial fibrillary acidic protein (GFAP) immunostaining, was obtained with 6KQ antibodies. We showed that P-gp was preferentially expressed in the endothelial component and Mrp1 in the astroglial component of the blood-brain barrier. Moreover, Mrp1 was rather expressed than P-gp in parenchyma astrocytes and in glia limitans lining the meninges. These findings provide new insights into the cerebral distribution of two ABC transporters linked to multidrug resistance (MDR).     

Dopamine in the lateral hypothalamus may be involved in the inhibition of locomotion related to food and water seeking

Experiments were conducted in male rats to assess the motor effects of bilateral intraperifornical microinjections of sulpiride, dopamine (DA) and other drugs. Sulpiride increased locomotion of the animals in all the experiments reported here. DA (10 micrograms) administered 5 minutes before sulpiride (8 micrograms) reduced the motor stimulant effect of the neuroleptic from 1601.3 +/- 337.6 to 742.5 +/- 180.4 counts/30 min. SCH 23390 (15 micrograms), haloperidol (2.5 micrograms) and atropine (18 micrograms) did not modify the locomotion level of animals acclimated to the actimeters. After carbachol (5 micrograms) the animals attained a level of hyperactivity (1459.5 +/- 146.5 counts/30 min) similar to that induced by sulpiride (1595.7 +/- 365.7 counts/30 min) in the same experiment. In other experiments DA (10 micrograms) administered 30 min before sulpiride again blocked the effect of 8 micrograms of sulpiride, and reduced the initial hyperactivity of food- and water-deprived animals previously familiarized with the actimeters (922.4 +/- 49.38 counts/15 min under saline, vs. 544 +/- 29 counts/15 min under DA). The same DA dose did not modify the initial spontaneous activity of nonfamiliarized nonfood-deprived rats (508.9 +/- 96.1 after saline vs. 520.9 +/- 47.1 after DA). These results suggest the presence of cells in the lateral hypothalamus involved in the control of locomotion. These experiments also suggest that locomotion triggered by the LH may be exploratory behavior essential to the search for water and food. As a corollary, DA in the LH appears to be involved not only in the inhibition of feeding and drinking but also in the inhibition of exploratory and food- and water-directed locomotion.     

Differences in behavior between surface and cave Astyanax mexicanus may be mediated by changes in catecholamine signaling

Astyanax mexicanus is a teleost fish that is in the process of allopatric speciation. Ancestral Astyanax are found in surface rivers and derived blind forms are found in cave systems. Adaptation to life in nutrient poor caves without predation includes the evolution of enhanced food seeking behaviors and loss of defensive responses. These behavioral adaptations may be mediated by changes in catecholaminergic control systems in the brain. We examined the distribution of tyrosine hydroxylase, a conserved precursor for the synthesis of the catecholamines dopamine and noradrenaline, in the brains of surface and cave Astyanax using immunohistochemistry. We found differences in tyrosine hydroxylase staining in regions that are associated with nonvisual sensory perception, motor control, endocrine release, and attention. These differences included significant increases in the diameters of tyrosine hydroxylase immunoreactive soma in cave Astyanax in the olfactory bulb, basal telencephalon, preoptic nuclei, ventral thalamus, posterior tuberculum, and locus coeruleus. These increases in modulation by dopamine and noradrenaline likely indicate changes in behavioral control that underlie adaptations to the cave environment.     

Effects of transcutaneous electrical nerve stimulation on memory and behavior in Alzheimer's disease may be stage-dependent.

BACKGROUND: In previous studies, transcutaneous electrical nerve stimulation (TENS) was shown to result in improvements in nonverbal short-term and long-term memory, verbal long-term memory, and verbal fluency in patients in an early stage of Alzheimer's disease (AD). In addition, the patients' physical, social, and affective functioning improved. As AD is a progressive disease, it was examined in the present study whether TENS would still be effective in the midstage of AD. METHODS: Sixteen subjects (70-91 years old) met the NINCDS-ADRDA criteria for probable AD, as well as the criteria for stage 6 of the Global Deterioration Scale (midstage AD). To evaluate treatment effects, the subjects underwent a number of neuropsychological tests and two observation scales. RESULTS: Compared to TENS in an early stage, TENS in the midstage of AD appears to yield less beneficial effects, i.e., as for cognition only nonverbal short-term memory improved. No treatment effects were observed for the patients' physical, social, and affective functioning. CONCLUSIONS: In view of the small number of patients, the clinical relevance of TENS in patients in a midstage of AD remains to be confirmed in a larger group, after which more definite conclusions about the stage-dependency of TENS in AD can be drawn.     

Polymorphism of CTLA-4 gene at position 49 of exon 1 may be associated with schizophrenia in the Korean population

This study was carried out to investigate the association of a polymorphism of the CTLA-4 gene, at position 49 of exon 1, with schizophrenia in the Korean population. Among Korean patients diagnosed with schizophrenia according to DSM-IV, 116 patients who met the selection criteria were recruited for the study. One hundred and forty-nine normal healthy Koreans from the Catholic Hemopoietic Stem Cell Information Bank, were used as a normal control group. DNA was extracted from whole blood using proteinase K and the CTLA-4 gene region was amplified by polymerase chain reaction. Geneo typing was performed by single strand conformation polymorphism (SSCP). The genotype and allele distribution in patients with schizophrenia was significantly different from that seen in the control group. This study suggests a putative role of the CTLA-4 gene polymorphism at position 49 of exon 1 for schizophrenia in the Korean population, although the detailed mechanisms remained to be elucidated.     

LGI1:一个与癫痫症和神经胶质瘤分级相关的基因

在2002年,人们首次证明了定位在10p24染色体中的富亮氨酸胶质瘤失活基因1(leucine-rich glioma inactivated gene 1,LGII)的基因突变会造成少见的特发性癫痫合症,即常染色体显性颞癫症(autosomal dominant lateral temporal epilepsy, ADLTE)[1-3].     

Cysteine- and glycine-rich protein 1a is involved in spinal cord regeneration in adult zebrafish

In contrast to mammals, adult zebrafish have the ability to regrow descending axons and gain locomotor recovery after spinal cord injury (SCI). In zebrafish, a decisive factor for successful spinal cord regeneration is the inherent ability of some neurons to regrow their axons via (re)expressing growth-associated genes during the regeneration period. The nucleus of the medial longitudinal fascicle (NMLF) is one of the nuclei capable of regenerative response after SCI. Using microarray analysis with laser capture microdissected NMLF, we show that cysteine- and glycine-rich protein (CRP)1a (encoded by the csrp1a gene in zebrafish), the function of which is largely unknown in the nervous system, was upregulated after SCI. In situ hybridization confirmed the upregulation of csrp1a expression in neurons during the axon growth phase after SCI, not only in the NMLF, but also in other nuclei capable of regeneration, such as the intermediate reticular formation and superior reticular formation. The upregulation of csrp1a expression in regenerating nuclei started at 3 days after SCI and continued to 21 days post-injury, the longest time point studied. In vivo knockdown of CRP1a expression using two different antisense morpholino oligonucleotides impaired axon regeneration and locomotor recovery when compared with a control morpholino, demonstrating that CRP1a upregulation is an important part of the innate regeneration capability in injured neurons of adult zebrafish. This study is the first to demonstrate the requirement of CRP1a for zebrafish spinal cord regeneration.