Naoko Narita

Serotonin Transporter Gene Variation Is a Risk Factor for Sudden Infant Death Syndrome in the Japanese Population

Objective. Serotonin (5-HT) in the nervous system is a major factor in facilitation of the brain center for respiration. Variations in the promoter region of the 5-HT transporter (5-HTT) gene have been shown to potentially regulate 5-HT activity in the brain. Therefore, we aimed to identify the possibility that specific allele variants of the 5-HTT gene can be found as a genetic background for sudden infant death syndrome (SIDS). Methods. Polymorphisms in the 5′ regulatory region of the 5-HTT gene were determined in genomic DNA obtained from 27 SIDS victims and 115 age-matched health control participants. Results. There were significant differences in genotype distribution and allele frequency of the 5-HTT promoter gene between SIDS victims and age-matched control participants. The L and XL alleles were more frequently found in SIDS victims than in age-matched control participants. Conclusion. Efficiency in the transportation of 5-HTT with the L allele is known to be higher than that with the S allele. The excitatory function by 5-HT is considered to be lower in the respiratory center of individuals with the L allele compared with those with S allele. The XL allele variant has shown another novel biological risk factor for SIDS.

Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism

Embryonic exposure to thalidomide (THAL) or valproic acid (VPA) before neural tube closure has been demonstrated as a useful model for human autism in rats. Abnormalities of the serotonergic system which are often observed in human autism have been shown in these rats. Thus, we examined whether early serotonergic neuronal development is perturbed by THAL/VPA. When pregnant rats were exposed to THAL or VPA on embryonic day 9, a dramatic shift of the distribution of serotonergic neurons in the dorsal raphe nucleus was observed on postnatal day 50. This alteration is thought to reflect abnormality of serotonergic neuronal differentiation and migration. In vitro studies revealed that VPA retards the maturation of serotonergic neuron from ES cell‐derived neuronal progenitors, whereas exogenously added Sonic hedgehog, a morphogen that has been implicated in serotonergic cell fate, partially prevented this retardation. These results indicate that disruption of early serotonergic neuronal development might be involved in the etiology of autism.

Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism.

Autism is defined as a congenital neurodevelopmental disorder in which serotonergic dysfunction may be involved in its pathogenesis. One of the characteristic laboratory findings in autistic patients is hyperserotonemia, although its mechanism has not been elucidated to date because of difficulties in studying human patients. Recent reports have demonstrated that thalidomide or valproic acid exposure during early embryonic days (first trimester) in humans causes higher incidence of autism. Morphologic abnormalities found in autism (e.g. cerebellar anomalies, reduced motor neuron numbers) have been reported in animals administered with these teratogens prenatally, suggesting the possibility of the use of these animals as an experimental autistic model. In this study, we evaluated monoamine levels in the brain and blood of rats exposed to teratogens prenatally. Of the groups exposed to thalidomide on embryonic day (E)2, E4, E7, E9, and E11, a significant increase of hippocampal serotonin was only observed in the group exposed on E9. Furthermore, E9 thalidomide and valproic acid exposure both resulted in an increase of hippocampal serotonin, frontal cortex dopamine, and hyperserotonemia. These results thus indicate that two potentially autism-inducing teratogens, thalidomide and valproic acid, have the same effect on early monoamine system development in the brain and the blood, which may explain the pathogenesis of autism.

Serum neurotrophin concentrations in autism and mental retardation: a pilot study.

To evaluate the availability of the serum neurotrophins for the diagnosis of the patients with neurodevelopmental disorder, we measured the serum concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) in the patients diagnosed with autism (n=18) and mental retardation (n=20), or healthy controls (n=16), using enzyme-linked immunosorbent assay. There tended to be a higher concentration of serum BDNF found in the autistic group ( P <0.05 by analysis of variance (ANOVA)) and the mental retardation group ( P <0.001 by ANOVA) compared to the control group. Serum NT-4 concentration tended to be increased in the mental retardation group (P <0.05 by ANOVA). We conclude that measuring the serum concentration of two neurotrophins, BDNF and NT-4, might be helpful to diagnose or classify disorders such as autism or mental retardation.

Modification of AMPA receptor properties following environmental enrichment

Environmental enrichment results in many modifications in the brain such as structural, behavioural, and biochemical changes. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptors for excitatory amino acid glutamate are recently found to be involved in neuronal plasticity. In this study, we examined whether environmental enrichment modified the brain expression of mRNA for subunit composition of AMPA receptors in adult mice using the real-time quantitative PCR method and western blotting. Mice housed in enriched environments showed significantly higher levels of GluR2 and GluR4 subunits in the hippocampus compared to control mice. We concluded that environmental enrichment can change the expression of AMPA receptor subunits and thus might modify the potentials of brain plasticity.

Nonexploratory movement and behavioral alterations in a thalidomide or valproic acid-induced autism model rat

Autism is a behaviorally characterized disorder with impairments in social interactions, as well as stereotyped, repetitive patterns of behaviors and interests. Exposure of rat fetuses to thalidomide (THAL) or valproic acid (VPA) on the ninth day of gestation has been reported as a useful model for human autism. We have shown that early serotonergic neural development is disrupted in these rats. In the current study, we used a radial maze and open field experimental paradigm to investigate whether these rats present behavioral and/or learning aberrations. THAL (500mg/kg), VPA (800mg/kg), or vehicle was administered orally to E9 pregnant rats at 7-10 weeks of age. Although the mean number of correct and incorrect arm choices in the initial eight arm choices did not differ between control and teratogen-exposed groups, achievement of learning (seven or eight consecutive correct choices for 3 consecutive days for individual rats) seemed to be impaired in teratogen-exposed groups. Interestingly, average time to explore the maze task was shorter in the teratogen-exposed groups, indicating that correct choice might be due to mere coincidence (i.e., nonexploratory movement). Unexpectedly, no significant differences were observed in social interaction in these rats. These results indicate that prenatal exposure to THAL and VPA might alter behavior in a manner that is, in part, consistent with human autism.

Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population

AimsRecent genetic studies have linked serotonin-related genetic polymorphisms with diverse disorders characterized by functional somatic symptoms, including chronic fatigue syndrome, irritable bowel syndrome, and premenstrual dysphoric disorder.MethodsWe investigated three serotonin-related genetic polymorphisms by screening genomic DNA of 36 temporomandibular disorder (TMD) patients.ResultsA significant increase of longer alleles (l and xl) was found in the TMD patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p < 0.01 by χ2 test and Fishers exact test).ConclusionGenetic factors that involve the serotonergic system may play a role in the pathogenesis of TMD.

Transcription factor GATA-4 is expressed in pediatric yolk sac tumors.

Yolk sac tumors (YSTs) are malignant tumors that occur in the gonads of children and young adults, and at extragonadal sites in young children. The histological features of YSTs are variable and can be superimposed on other germ cell tumor histologies. Malignant endodermal cells within YSTs express alpha-fetoprotein, which can be detected in tumor tissue or serum. However, additional markers of endoderm differentiation would be beneficial for the classification of these tumors. Transcription factor GATA-4 regulates the differentiation and function of murine yolk sac endoderm, and its expression correlates with proliferation and cell survival in certain tissues. To see whether GATA-4 plays a role in human YSTs, we surveyed its expression in human germ cell tumors and cell lines. Northern analysis demonstrated expression of GATA-4 mRNA in four human germ cell tumor lines exhibiting yolk sac endoderm differentiation. GATA-4 protein was detected in eight of nine pediatric YSTs by immunohistochemistry. Three of five immature teratomas exhibited GATA-4 in neural blastematous cells and in cylindrical epithelium, whereas all 16 mature teratomas were devoid of GATA-4. We conclude that GATA-4 is a clinically useful marker of human YSTs and speculate that it may play a role in the maintenance of the malignant phenotype.

A biogenic amine-synapse mechanism for mental retardation and developmental disabilities.

Recent studies have demonstrated that biogenic amines have a function of facilitating formation and maintenance of synapses in diverse regions of the central nervous system in developing and adult animals. The normal number of synapses maintained by biogenic amines are crucial to acquire learning and memory. The level of biogenic amines was reported to decrease in the brain by several neurodevelopmental disorders associated with mental retardation and developmental disabilities such as Rett syndrome, autism and Down syndrome. Taken into consideration this fact together with the function of biogenic amines for synapses, the density of synapses appears to decrease considerably in the brains of patients suffered from the neurodevelopmental disorders. The synaptic overproduction during the critical period of development especially 1 year after birth has been considered as a background mechanism to provide plasticity for the developing brain. Synaptic overproduction does not appear to occur in the brains of patients suffered from the neurodevelopmental disorders, which they are observed mental retardation occurring in the first 1 year after birth. Along with the neurodevelopmental disorders, environmental factors (stress, drugs and nutrition) during pre- and post-natal critical developmental periods are known to change levels of biogenic amines in the brain. In fact, maternal stress has been shown to decrease the levels of serotonin and the density of synapses in the hippocampus of the offspring, and they showed developmental disabilities in the spatial learning and memory. A cascade appears to exist from either the child neurological disorders or the environmental factors to mental retardation and developmental disabilities by decreases in the levels of biogenic amines and synaptic density.

Maternal viral infection during pregnancy impairs development of fetal serotonergic neurons.

BACKGROUND Maternal viral infection during pregnancy induces morphological abnormalities in the fetus and may cause emotional and psychological problems in offspring through unknown mechanisms. We have previously shown that prenatal exposure of rats to chemicals such as thalidomide causes an autistic-like phenotype in offspring, indicating that prenatal events affecting serotonergic development may cause developmental disorder. METHODS We investigated whether prenatal viral infection altered the expression of neurotransmitters involved in the emotional or psychological status of offspring. We here took advantage of the polyriboinosinic:polyribocytidylic acid (poly I:C) system, the synthetic double-stranded RNA, which is often used in animal models of viral infection. RESULTS Ten mg/kg of poly I:C was intraperitoneally injected on gestational day (GD) 9 and counted the numbers of serotonin-immunopositive cells on GD15 using flat whole-mount preparation method, resulting 11.1% of increase in the number of serotonergic neurons in poly I:C group. Furthermore, there was a significant decrease in hippocampal serotonin content in offspring by postnatal day 50 following poly I:C administration by high-performance liquid chromatography. DISCUSSION AND CONCLUSION Since serotonin is known to link with behavior and emotion after birth, these results suggest that maternal viral infection might cause, in addition to morphological abnormalities, serotonin-related pathogenesis such as neurodevelopmental disorders including autism spectrum disorders.