Asahikawa Medical University

Depression includes different phenotypes. Modern-type depression (MTD) is a gateway disorder to pathological social withdrawal, known as hikikomori. Adverse childhood experiences (ACEs) are also important aetiologies of depression. Recently, immune imbalance has been proposed as a biological basis of depression. We hypothesised that peripheral immunological characteristics may be involved in subtyping of depression.

21 patients with major depressive disorder (MDD) and 24 healthy controls (HC) were recruited. Peripheral blood mononuclear cells (PBMCs) were examined for surface antigens by flow cytometry. Participants were administered psychological scales such as Patient Health Questionnaire (PHQ)-9, Modern-Type Depression Trait Scale (TACS-22), Hikikomori Questionnaire (HQ-25), Child Abuse and Trauma Scale (CATS).

MDD group showed significantly higher percentage of B cells than HC group (p = 0.032). MDD group presented a negative correlation between: PHQ-9 and CD8 T effector memory cells (r= -0.639, p = 0.002), TACS-22 and monocytes (r= -0.459, p = 0.036), HQ-25 and NK T cells (r= -0.638, p = 0.004), CATS and Intermediate monocytes (r= -0.594, p = 0.009).

MTD traits, hikikomori tendencies, and ACEs were correlated with specific characteristics of peripheral immune cells. Our results suggest that immune imbalance influences the diverse presentations of depression. Further validation is warranted by large-scale prospective studies.

Leaky gut is implicated in disorders such as irritable bowel syndrome (IBS) and Alzheimer's disease (AD). Our previous study demonstrated that brain histamine H1 receptor signaling-mediated via basal forebrain cholinergic neurons (BFCNs), adenosine A2B receptors, and the vagus nerve-regulates intestinal barrier function. In this study, we investigated the role of carnosine, a dipeptide composed of beta-alanine and L-histidine, in modulating intestinal barrier integrity. In an LPS-induced leaky gut rat model, intracisternal administration of carnosine improved colonic permeability as determined by the Evans blue dye method. This effect was abolished by brain H1 receptor antagonism, vagotomy, and inhibition of either BFCNs or adenosine A2B signaling, suggesting that carnosine acts via these central pathways. Similarly, high-dose intraperitoneal carnosine alleviated colonic hyperpermeability, with its effect also blocked by the same interventions. Additionally, exercise reduced LPS-induced hyperpermeability-an effect eliminated by brain histamine H1 receptor blockade. These findings indicate that peripheral carnosine, including muscle-derived carnosine, contributes to the central regulation of the intestinal barrier. Enhanced barrier integrity, which reduces visceral hypersensitivity, suggests that carnosine may be an effective therapeutic for IBS. Moreover, the decline in muscle carnosine observed in sarcopenia, coupled with an increased dementia risk, supports its therapeutic potential for AD. Collectively, the present study underscores the promise of carnosine and muscle-derived strategies in managing leaky gut-related disorders.

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder caused by duplication or extra copies of MECP2 gene. It primarily affects males and is characterized by intellectual disability, hypotonia, epilepsy, recurrent infections, and autistic features. Methyl-CpG binding protein 2 (MeCP2) encoded by MECP2 is a crucial epigenetic regulator of brain function. Expression levels are strictly regulated during brain development and maturation, and altered levels lead to severe neurodevelopmental disorders; excessive levels are associated with MDS, while insufficient levels cause Rett syndrome. This review provides a comprehensive overview of the recent advances in the pathophysiology and therapeutic perspectives of MDS, focusing on its pathophysiology, clinical features, disease models, and therapeutic strategies. Advances in studies using animal and patient-derived induced pluripotent stem cells (iPSCs)-derived neuronal models have provided insights into the molecular and cellular abnormalities associated with MDS and have facilitated therapeutic development. Among the emerging treatments, antisense oligonucleotide (ASO) therapy has gained significant attention as a promising approach for selectively suppressing MeCP2 overexpression. Preclinical studies using MDS mouse models and iPSCs-derived neurons have demonstrated that ASO treatment can partially restore neuronal abnormalities and clinical trials are currently underway.