Molecular Psychiatry最新文献

Phelan-McDermid Syndrome (PMS), primarily linked to SHANK3 haploinsufficiency, presents with complex neurodevelopmental features, including developmental regression, whose underlying mechanisms are poorly understood. This study investigated the impact of SHANK3 disruption across multiple levels, from gene expression in patient-derived iPSC neurons to in vivo brain network activity. RNA-sequencing of iPSC-derived neurons from PMS patients with SHANK3 disruption only (n = 9) and controls (n = 7) revealed dysregulation in differential gene expression and co-expression modules linked to cell cycle, RNA metabolism, and metabolic pathways in SHANK3-mutated neurons. All modules were correlated with PMS regression and enriched for genes implicated in neurodevelopmental or neurodegenerative disorders, such as autism, ADHD, and Alzheimer's disease. At the cellular level, SHANK3-mutated cultures exhibited increased proliferation of neural progenitors and intermediate progenitor markers. Differentiated neurons showed reduced morphological complexity, specific changes in postsynaptic marker density and puncta size, and electrophysiological characteristics suggestive of neuronal hyperexcitability. Electroencephalography (EEG) in a PMS patient cohort (n = 20) compared to controls (n = 30) demonstrated hyperconnectivity and excessive high-frequency oscillations, suggesting altered neural network dynamics. In summary, the use of different analytical approaches suggested that SHANK3 haploinsufficiency disrupts neurodevelopmental trajectories and revealed that regression in PMS may share common genes and pathways with neurodegeneration. We also characterized molecular and neurophysiological markers that can be useful in therapeutic protocols for PMS.

The genetic relationship between schizophrenia, IQ, and educational attainment (EA) is complex. Schizophrenia polygenic scores (PGS) are linked to lower IQ, whilst higher IQ-PGS correlates with reduced schizophrenia risk. Paradoxically, genetic predisposition to higher EA has been associated with increased schizophrenia risk, a relationship potentially confounded by genetic overlap between schizophrenia and bipolar disorder. Using a latent-variable Genomic Structural Equation Modelling approach to GWAS summary statistics for schizophrenia and bipolar disorder, we dissected the genetic contribution to schizophrenia, identifying 63 SNPs specifically associated with schizophrenia (SZ_specific) and 78 shared with bipolar disorder (PSY_shared). Both schizophrenia (rg = -0.22) and SZ_specific (rg = -0.24) were genetically negatively correlated with IQ; correlations between bipolar disorder and PSY_shared with IQ were less pronounced (both rg = -0.07). Schizophrenia exhibited no correlation with EA, yet the latent variables demonstrated divergent relationships; PSY_shared was positively correlated (rg = 0.11), whereas SZ_specific was negatively correlated (rg = -0.06). PGS analyses in the UK Biobank (n = 381,688), corroborated these divergent relationships, SZ_specific-PGS was negatively associated with EA (β = -0.13, p < 2e-16), whereas the PSY_shared-PGS was positively associated (β = 0.14, p < 2e-16). Mendelian randomisation provided additional support but also confirmed the presence of genetic pleiotropy. These findings underscore the utility of genetic methods in dissecting the heterogeneity of neuropsychiatric disorders, supporting the existence of two possible pathways to schizophrenia: one shared with bipolar disorder and another with greater neurocognitive impact.

Schizophrenia, a chronic psychiatric disorder, has prompted extensive research into its immunological aspects. Studies in genetics, epidemiology, and treatment have revealed immune changes associated with schizophrenia, including shifts in cytokine levels and microglial reactivity within the central nervous system (CNS). However, the term "neuroinflammation" has been used to describe these findings despite inconsistent classical markers, potentially oversimplifying the complex role of immune mediators in neurodevelopment and brain homeostasis. In this paper, we critically examine the limitations of applying "neuroinflammation" to describe immune changes in schizophrenia, focusing on its four classical hallmarks: elevated cytokines, microglial reactivity, peripheral immune cell infiltration, and neurodegeneration. While some alterations in these markers are reported, many findings fall within clinical norms or likely contribute to neurodevelopment, suggesting that the term "neuroinflammation" may misrepresent their role. Instead, we propose using alternative terminology that reflects the broader spectrum of CNS immune responses, both inflammatory and non-inflammatory, and invite the scientific community to join this dialogue to refine terminology. By reframing immune alterations in schizophrenia, we aim to promote accuracy and consistency across medical disciplines, ensuring terminology that accurately represents the underlying biology. This, in turn, will improve communication among researchers and clinicians.

Polychlorinated biphenyls (PCBs) are highly stable synthetic organic compounds that are present in air, water, and soil. PCBs have been identified in post-mortem human brains, indicating a possible link between environmental factors and disease risk. Research has revealed an association between PCB exposure and cognitive decline. Therefore, it is crucial to evaluate how PCB mixtures relevant to humans affect brain function and cognition. To investigate the effects of PCBs on memory and transcriptomic profiles, we exposed male C57BL/6 J mice orally to a synthetic PCB mixture daily. After seven weeks of exposure, the adult mice were assessed in a spatial object recognition task (SOR) to evaluate long-term spatial memory. Our findings showed that mice exposed to PCBs exhibited deficits in long-term spatial memory. To examine the molecular effects of PCB on the brain, we used a spatial transcriptomics technique to analyze gene expression changes in five brain regions: the hippocampus, neocortex, thalamus, caudal putamen, and fiber tracts. Our analysis of spatial gene expression revealed the molecular signatures influenced by PCB in these susceptible brain regions of mice. Network analysis suggests that these changes are associated with higher chlorinated PCBs present in the brain. Additionally, we show that PCB exposure disrupts the expression of tight junction proteins, which are crucial for maintaining the integrity of the blood-brain barrier (BBB). Thus, our results offer mechanistic insights into how PCB exposure affects brain function and cognition.

Aerobic glycolysis (AG) refers to the preferential use of glucose through glycolysis and not oxidative phosphorylation (OxPhos) despite the presence of oxygen. Originally described in cancer cells as the Warburg effect, AG is now recognized as a broader physiological mechanism extending beyond cancer biology. This process is less efficient than OxPhos in terms of ATP yield, but supports biosynthesis, neural plasticity, oxidative stress reduction, and synaptogenesis under metabolically demanding conditions. Building on this physiological role and current findings, we propose that in schizophrenia (SZ), AG remains elevated in adulthood, likely reflecting a compensatory response to reduced brain biomass and mitochondrial dysfunction. Neuroimaging, spectroscopy, and postmortem studies link the presence of AG in the brain to impaired OxPhos, reductive stress and defective neuron-glia coupling. Oligodendrocyte dysfunction and white matter damage also additionally compromise energy homeostasis and connectivity. Though AG supports repair, its persistent activation may destabilize synaptic structures and function. This Perspective proposes that AG in SZ represents a mismatch between developmental demands and adult metabolic function, compensatory in early stages but ultimately (mal)adaptive. Understanding when, where and why AG persists may reveal new entry points for restoring energetic balance in vulnerable brain circuits.

Depression leads to complex changes in protein regulation in the brain and other tissues. Reproducibility and data integration remain challenges in this field. We systematically integrated proteomic data from our previous established database Pro-MENDA, encompassing brain, cerebrospinal fluid (CSF), blood, and urine samples from patients with depression. Using a vote-counting statistics to assess consistency of protein expression changes across studies, we identified 2094 different expression proteins from 1804 samples. Functional characterization included Gene Ontology, KEGG pathway enrichment, protein-protein interaction analysis, and post-translational modification. In brain, we observed changes in proteins related to synaptic function and energy metabolism, such as Glial fibrillary acidic protein (GFAP) and Histidine triad nucleotide-binding protein 1 (HINT1). These changes suggest issues with oxidative phosphorylation and synaptic activity. The CSF and blood revealed immune-inflammatory markers like Afamin (AFM) and Serpin Family F Member 1 (SERPINF1), while urine analysis showed signs of neutrophil activation. We also identified 13 shared proteins across brain, CSF, and blood, including Clusterin (CLU), that link complement and coagulation, and reactive oxygen pathways. In this protein-protein interaction network of brain, proteins related to cell adhesion, respiration, neuron and synapse are significantly enriched. Post-translational modifications, particularly phosphorylation, were common. Our findings highlight systemic protein dysregulation in depression. This connects brain and peripheral mechanisms, offering insights for identifying multi-tissue biomarkers and developing targeted therapies.

Maternal infections during pregnancy may impact offspring brain development and increase the risk of mental disorders, but their impact on suicidal behavior remains unclear. In this study, we investigated associations between maternal infections before, during, and after pregnancy and offspring suicide attempt later in life to understand the mechanisms explaining these associations. Furthermore, paternal infections during these same periods were examined to pinpoint the possible specific role of intra-uterine exposure vs. genetic and socioeconomic confounding factors. A cohort design was applied to individual-level register-based data including all persons aged 10+ years and living in Denmark in 1987-2021. Information on maternal infection (bacterial, viral, and other, as well as at different body sites) was obtained from the Medical Birth Register based of diagnoses received during hospital contacts. The main outcome was hospital presentations for suicide attempt in the offspring. Adjusted Incidence Rate Ratios (IRR) were estimated to quantify the association between exposure to maternal infections and offspring suicide attempt. Of 2,157,641 individuals (35,047,803 person-years), 38,840 (1.8%), 26,158 (1.2%), and 34,853 (1.6%), had been exposed to maternal infection during, before, and after pregnancy, respectively, while 32,275 attempted suicide. Rates among those exposed to maternal infection during pregnancy and those non-exposed were 141.2 and 90.0 per 100,000 person-years, respectively. After adjustment, individuals exposed to maternal infections during pregnancy had higher risk of suicide attempt when compared to non-exposed (IRR 1.46 [1.36-1.56]), particularly those exposed in the second and third trimesters. Elevated risks were also observed among individuals whose mothers with infections prior (incidence rate: 144.3 per 100,000; IRR 1.45 [1.33-1.57]) and after pregnancy (incidence rate: 128.3 per 100,000; IRR 1.31 [1.21-1.42]). However, no associations were found for paternal infections during, before, or after pregnancy and offspring suicide attempt. These findings show that maternal, but not paternal, infections were associated with later risk of suicide attempt in the offspring, pointing out to a possible role of the intra-uterine environment. The similar estimates obtained for exposure to maternal infections before and after pregnancy suggests that part of this risk may stem from an underlying susceptibility to infections or socioeconomic confounding factors, as well as to possible measurement errors in the onset of infections.

Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and has been implicated in major neurological diseases. The brain is enriched in polyunsaturated fatty acids (PUFAs) and iron, which makes it particularly susceptible to lipid peroxidation, leading to ferroptosis. In neurological diseases such as Alzheimer's disease (AD) and stroke, such mechanisms are dysregulated and contribute to neuronal loss. Physiologically, the lipid peroxidation resistance systems in the brain, including defenses (such as SOD, CAT, Prxs, GPxs) and repair systems (such as GPx4, FSP1), prevent ferroptosis and repair damaged phospholipid membranes. However, the efficacy of endogenous resistance systems is often compromised in pathological states, positioning exogenous antioxidants as promising therapeutic candidates. Future research could optimize the delivery of these compounds and explore new candidates that specifically target the ferroptosis signaling pathway to prevent neurodegeneration occurring in neurological diseases.

Stress-related psychiatric disorders impact the quality of life of half a billion people around the world. However, our understanding of the molecular mechanisms responsible for stress-response regulation remain unclear. Here, we report the largest and most comprehensive characterization of the adult male mouse hippocampus, under baseline and acute stress condition, using single-cell RNA sequencing. We further used genetically modified knockout lines for the glucocorticoid and mineralocorticoid receptors (GR and MR); two transcription factors which are pivotal regulators of the central stress-response. We found previously unknown, cell-type specific, molecular signatures of a single prolonged social defeat stress response and identified Nrgn and SgK1 as key regulators in stress-responsive glutamatergic neurons, oligodendrocytes, astrocytes, and endothelial cells. Intriguingly, GR or MR deletion, specifically in glutamatergic or GABAergic neurons, led to distinct and cell-type specific transcriptional signatures after stress exposure. This study significantly advances our understanding of the molecular and cellular network underlying the central response to stressful stimuli.