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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.

Filamin A-interacting protein (FILIP in mice, FILIP1 in humans) was first identified as a protein that negatively controls neuronal migration in rodents, and was subsequently demonstrated to be pivotal for the development of the neocortex. In the previous study, we generated FILIP knockout mice to investigate the in vivo functions of FILIP in cortical development. Since FILIP mRNA is widely expressed in the body, we systematically examined FILIP-knockout mice to determine the functions of FILIP throughout the body. Our results showed that FILIP-knockout mice exhibited weak grip strength and sensory abnormalities. Interestingly, we also found that FILIP was expressed in a subset of neurons in the dorsal root ganglion (DRG). Recent research has reported that FILIP1 mutations lead to severe neurological and musculoskeletal abnormalities, resulting in the proposal of a new disease entity, termed FILIP1opathy. It is expected that our FILIP-knockout mice could be used as a model for the pathological investigation of FILIP1opathy.