Disrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.
An increase in glucocorticoid levels and down-regulation of BDNF (brain-derived neurotrophic factor) are supposed to be involved in the pathophysiology of depressive disorders. However, possible crosstalk between glucocorticoid-and BDNF-mediated neuronal functions in the CNS has not been elucidated. Here, we examined whether chronic glucocorticoid exposure influences BDNF-triggered intracellular signaling for glutamate release via a glutamate transporter. We found that chronic exposure to dexamethasone (DEX, a synthetic glucocorticoid) suppressed BDNF-induced glutamate release via weakening the activation of the PLC-␥ (phospholipase C-␥)/Ca 2؉ system in cultured cortical neurons. We demonstrated that the GR (glucocorticoid receptor) interacts with receptor tyrosine kinase for BDNF (TrkB). Following DEX treatment, TrkB-GR interaction was reduced due to the decline in GR expression. Corticosterone, a natural glucocorticoid, also reduced TrkB-GR interaction, BDNF-stimulated PLC-␥, and BDNF-triggered glutamate release. Interestingly, BDNF-dependent binding of PLC-␥ to TrkB was diminished by DEX. SiRNA transfection to induce a decrease in endogenous GR mimicked the inhibitory action of DEX. Conversely, DEX-inhibited BDNF-activated PLC-␥ signaling for glutamate release was recovered by GR overexpression. We propose that TrkB-GR interaction plays a critical role in the BDNF-stimulated PLC-␥ pathway, which is required for glutamate release, and the decrease in TrkB-GR interaction caused by chronic exposure to glucocorticoids results in the suppression of BDNF-mediated neurotransmitter release via a glutamate transporter.
An increased level of glucocorticoid may be related to the pathophysiology of depressive disorder. The involvement of brain-derived neurotrophic factor (BDNF) in the antidepressive effect has also been suggested; however, the possible influence of glucocorticoid on the action of BDNF in the developing central nervous system has not been elucidated. In this study, we investigated the effect of glucocorticoid (dexamethasone, DEX) on synaptic maturation and function enhanced by BDNF in early developing hippocampal neurons. In the immature stage, BDNF increased the outgrowth of dendrites and the expression of synaptic proteins including glutamate receptors and presynaptic proteins. Pretreatment with DEX significantly inhibited the BDNF-dependent up-regulation of both dendritic outgrowth and synaptic proteins. In the more mature stage, the BDNF-reinforced postsynaptic Ca(2+) influx was decreased by DEX. BDNF-enhanced presynaptic glutamate release was also suppressed. RU486, a glucocorticoid receptor antagonist, canceled the DEX-dependent blocking effect on the action of BDNF. After down-regulation of glucocorticoid receptor by small interfering RNA application, no inhibitory effect of DEX on the BDNF-increased synaptic proteins was observed. Interestingly, the BDNF-activated MAPK/ERK pathway, which is an essential intracellular signaling pathway for the BDNF-increased synaptic proteins, was reduced by DEX. These results suggest that BDNF-mediated synaptic maturation is disturbed after neurons are exposed to high-level glucocorticoid in their development stage.
Identification of vocalizers was examined using an auditory-visual matching-to-sample task with a female chimpanzee. She succeeded in selecting the picture of the vocalizer in response to various types of vocalizations: pant hoots, pant grunts, and screams. When pant hoots by two chimpanzees were presented as a "duet", she could identify both of the vocalizers. These results suggest that researchers have underestimated the capability of vocalizer identification in chimpanzees. The chimpanzee correctly chose her own pictures in response to her vocalizations only by exclusion, and she did not show vocal self-recognition. The effect of acoustical modification (pitch shift and filtration) on the performance suggested that pitch is an important cue for the vocalizer identification.
Consonance/dissonance affects human perception of chords from early stages of development [e.g., Schellenberg and Trainor, J. Acoust. Soc. Am. 100, 3321-3328 (1996)]. To examine whether consonance has some role in audition of nonhumans, three Japanese monkeys (Macaca fuscata) were trained to discriminate simultaneous two-tone complexes (chords). The task was serial discrimination (AX procedure) with repetitive presentation of background stimuli. Each tone in a chord was comprised of six harmonics, and chords with complex ratios of fundamental frequency (e.g., frequency ratio of 8:15 in major seventh) resulted in dissonance. The chords were transposed for each presentation to make monkeys attend to cues other than the absolute frequency of a component tone. Monkeys were initially trained to detect changes from consonant (octave) to dissonant (major seventh). Following the successful acquisition of the task, transfer tests with novel chords were conducted. In these transfer tests, the performances with detecting changes from consonant to dissonant chords (perfect fifth to major seventh; perfect fourth to major seventh) were better than those with detecting reverse changes. These results suggested that the consonance of chords affected the performances of monkeys.
Auditory-visual processing of species-specific vocalizations was investigated in a female chimpanzee named Pan. The basic task was auditory-visual matching-to-sample, where Pan was required to choose the vocalizer from two test movies in response to a chimpanzee's vocalization. In experiment 1, movies of vocalizing and silent faces were paired as the test movies. The results revealed that Pan recognized the status of other chimpanzees whether they vocalized or not. In experiment 2, two different types of vocalizing faces of an identical individual were prepared as the test movies. Pan recognized the correspondence between vocalization types and faces. These results suggested that chimpanzees possess crossmodal representations of their vocalizations, as do humans. Together with the ability of vocal individual recognition, this ability might reflect chimpanzees' profound understanding of the status of other individuals.
Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n ¼ 439), major depression (n ¼ 409), bipolar disorder (n ¼ 207), and controls (n ¼ 727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n ¼ 166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3 0 regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P ¼ 0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P ¼ 0.016) and verbal IQ (Po0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.
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