Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death

Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-d-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave–ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced γ-aminobutyric acid (GABA) levels, and the persistent 30–50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker α-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy.National Institutes of Health (U.S.). Intramural Research ProgramNational Institutes of Health (U.S.) (Grant R01-MH078821)Japan Society for the Promotion of Scienc

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Use of human methylation arrays for epigenome research in the common marmoset (Callithrix jacchus)

tWe examined the usefulness of commercially available DNA methylation arrays designed for the humangenome (Illumina HumanMethylation450 and MethylationEPIC) for high-throughput epigenome analysisof the common marmoset, a nonhuman primate suitable for research on neuropsychiatric disorders. Fromamong the probes on the methylation arrays, we selected those available for the common marmoset. DNAmethylation data were obtained from genomic DNA extracted from the frontal cortex and blood samplesof adult common marmosets as well as the frontal cortex of neonatal marmosets. About 10% of the probeson the arrays were estimated to be useful for DNA methylation assay in the common marmoset. Strongcorrelations existed between human and marmoset DNA methylation data. Illumina methylation arraysare useful for epigenome research using the common marmoset

Relationship between high trait anxiety in 22q11.2 deletion syndrome and the difficulties in medical, welfare, and educational services

Abstract Aim The 22q11.2 deletion syndrome (22q11DS) is associated with a high prevalence of mental health comorbidities. However, not enough attention has been paid to the elevated prevalence of high trait anxiety that begins early in life and may be enduring. We sought to identify specific medical, welfare, or educational difficulties associated with high trait anxiety in 22q11DS. Methods A questionnaire‐based survey was conducted for the parents of 22q11DS individuals (N = 125). First, a multiple regression analysis was conducted to confirm the hypothesis that high trait anxiety in individuals with 22q11DS would be associated with parents' psychological distress. This was based on 19 questionnaire options regarding what difficulties the parents currently face about their child's disease, characteristics, and traits. Next, we explored what challenges faced in medical, welfare, and educational services would be associated with the trait anxiety in their child. Results The multiple regression analysis confirmed that the high trait anxiety was significantly associated with parental psychological distress (β = 0.265, p = 0.018) among the 19 clinical/personal characteristics of 22q11DS. Furthermore, this characteristic was associated with various difficulties faced in the medical care, welfare, and education services, and the parent–child relationship. Conclusion To our knowledge, this is the first study to clarify quantitatively how the characteristic of high anxiety level in 22q11DS individuals is related to the caregivers' perceived difficulties in medical, welfare, and educational services. These results suggest the necessity of designing service structures informed of the fact that high trait anxiety is an important clinical feature of the syndrome

Population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC):Cohort longitudinal study to explore the neurobiological substrates of adolescent psychological and behavioral development.

Adolescence is a crucial stage of psychological development and is critically vulnerable to the onset of psychopathology. However, our understanding of how maturation of endocrine, epigenetics, and brain circuit may underlie the psychological development in adolescence has not been integrated. Here, we introduce our research project, the "population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC)," a longitudinal study to explore the neurobiological substrates of development during adolescence