Satoko Hattori

Abstract Proper maturation of neuronal and glial cells in the hippocampus is essential for emotional regulation and cognitive function. While pseudo-immaturity, defined as arrested or reversed development, has been extensively implicated in various neuropsychiatric conditions, the opposite phenomenon, hyper-maturity, remains underexplored. Here, we present transcriptomic evidence of hippocampal hyper-maturity across 17 datasets from 16 mouse models with genetic, pharmacological, or other experimental manipulations, identified through a comprehensive screening of over 260,000 omics datasets. These models were characterized by a pronounced overrepresentation of gene expression changes typically observed during postnatal development and included serotonin transporter knockout mice, glucocorticoid receptor overexpressing mice, and corticosterone-treated mice, models of depression and anxiety, Df(16)A ^+/− mice, a 22q11.2 deletion schizophrenia model, β-glucuronidase-deficient lysosomal storage disorder model mice, and senescence-prone SAMP8 mice. Meta-analysis of enriched pathways highlighted associations of synapse-related genes with the hyper-maturity signature. Behavioral annotations from public datasets further suggest that hippocampal hyper-maturity models predominantly exhibit increased anxiety-like behaviors, whereas immaturity models tend to display the opposite pattern. Notably, hippocampal hyper-maturity encompassed two transcriptional dimensions: enhanced postnatal development and accelerated aging. For example, SAMP8 mice aligned more with developmental enhancement, whereas corticosterone-treated and lysosomal storage disorder models reflected aging acceleration. Combined analysis with available single-cell RNA-sequencing data further delineated that microglia and granule cells may contribute to aging-associated transcriptional shifts. These findings suggest that hippocampal hyper-maturity and accelerated aging represent convergent molecular phenotypes associated with anxiety-like behavior. Bidirectional alterations in hippocampal maturity may serve as a transdiagnostic endophenotype and offer novel therapeutic or anti-aging targets for neuropsychiatric disorders.

BACKGROUND: Genomic analyses of psychiatric disorders, including autism spectrum disorder (ASD), have revealed many susceptibility genes, suggesting that such disorders may be caused by multiple factors. In this sense, it has long been a question whether there is an abnormal genetic status that comprehensively explains the pathogenesis of neuropsychiatric disorders or a"promising upstream treatment target"that normalizes symptoms. METHODS: To address this question, we provide important clues with respect to GASC1 (JMJD2 C/KDM4 C), which is a histone demethylase that prominently targets trimethylated histone H3 at lysine 9 (H3 K9 me3). Gasc1 hypomorphic mutant mice were analyzed using molecular biological, biochemical, behavioral battery tests, histological, and electrophysiological techniques. RESULTS: Mice homozygous for a hypomorphic mutation in Gasc1 exhibited abnormal behaviors, including hyperactivity, stereotyped behaviors, and impaired learning and memory, which are reminiscent of those of human psychiatric disorders. Electrophysiological studies of hippocampal slices revealed decreased paired-pulse facilitation and enhanced long-term potentiation, suggesting synaptic dysfunction in the mutants. Increased dendritic spine density in CA1 neurons was also detected in the mutants. Intriguingly, genetic linkage studies of human ASD have mapped a susceptibility locus on chromosome 9p24.1, which contains 78 genes, including the GASC1 gene. CONCLUSION: Taken together, our data suggest that histone demethylation plays a pivotal role in normal brain development and higher-order brain functions in both mice and humans.

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia (CHN) may induce neurological manifestations, including psychological symptoms. However, the specific psychological symptoms induced by CHN, the mechanisms underlying these symptoms, and their potential reversibility remain unclear. Therefore, this study aimed to determine whether monoaminergic neurotransmission is associated with innate anxiety-like behaviors potentiated by CHN in a mouse model of CHN secondary to the syndrome of inappropriate antidiuresis. In the present study, using a mouse model of the syndrome of inappropriate antidiuresis presenting with CHN, we showed that the sustained reduction of serum sodium ion concentrations potentiated innate anxiety-like behaviors in the light/dark transition and open field tests. We also found that serotonin and dopamine levels in the amygdala were significantly lower in mice with CHN than in controls. Additionally, phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala was significantly reduced in mice with CHN. Notably, after correcting for CHN, the increased innate anxiety-like behaviors, decreased serotonin and dopamine levels, and reduced phosphorylation of ERK in the amygdala were normalized. These findings further underscore the importance of treating CHN and highlight potential therapeutic strategies for alleviating anxiety in patients with CHN, which will improve their quality of life.