Mol. Psychiatry [JOURNAL]
Sun
200 papers
Circulating lipids are related to longitudinal changes of ATN biomarkers for Alzheimer's disease.
Kim JP, Nho K, Wang T … +14 more , Huynh K, Arnold M, Risacher SL, Bice PJ, Han X, Kristal BS, Blach C, Baillie R, Kastenmüller G, Meikle PJ, Saykin AJ, Kaddurah-Daouk R, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Metabolomics Consortium (ADMC)
Mol Psychiatry · 2026 Jun · PMID 42304066 · Publisher ↗
Investigating the relationship of circulating lipidome profiles with cross-sectional and longitudinal changes of central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a...
Investigating the relationship of circulating lipidome profiles with cross-sectional and longitudinal changes of central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD pathophysiology. In this study, we quantified a total of 749 plasma lipid species at baseline using liquid chromatography-mass spectrometry and performed cross-sectional and longitudinal association analysis of plasma lipidome profiles with longitudinal A/T/N biomarkers for AD in the Alzheimer's Disease Neuroimaging Initiative cohort (N = 1395). We identified several lipid species, classes, and network modules of correlated lipids that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers. Notably, we identified lysoalkylphosphatidylcholine (LPC(O)) as associated with cross-sectional "A/N" biomarkers at the lipid species, class, and module levels. Also, Phosphatidylethanolamine (PE) ethers were associated with A/T/N biomarkers in the species level and with "N" biomarkers in the class and module levels. G ganglioside showed association with cross-sectional and longitudinal changes of "N" biomarkers at the species and class levels. Furthermore, 20 lipid species, out of all 57 species identified as associated with "less severe" AD biomarkers, contained docosahexaenoic acid (DHA), indicating that the previously reported beneficial effects of DHA on AD were significant at the central biomarker level. In conclusion, our approach linking peripheral metabolic changes with brain metabolic, structural, and functional states strengthens evidence from previous studies that were performed using only clinical AD diagnosis. Importantly, our study also enabled identification of novel lipids that play potential roles in progression of AD pathophysiology, suggesting dysregulation of lipid metabolic pathways as precursors to AD development and progression.
Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication.
Ko SY, Pastore SF, Park S … +9 more , Epp JR, Mikhailov A, French L, Harada H, Monnier PP, Hamel PA, Josselyn SA, Vincent JB, Frankland PW
Mol Psychiatry · 2026 Jun · PMID 42297937 · Publisher ↗
PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1) exhibit hyperactivity and learning impairments, but do not rec...
PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that PTCHD1 exon 3 is a high-risk locus. We therefore generated an alternative Ptchd1 knockout mouse model by targeting Ptchd1 exon 3 (Ptchd1) using CRISPR/Cas9. Our analyses revealed that two major PTCHD1/Ptchd1 transcripts-a (full-length) and c (shorter)-were expressed in the brain. In Ptchd1 mice, Ptchd1_a was lost, but Ptchd1_c was compensatorily upregulated, and these mice showed no ASD-like social deficits. In Ptchd1 mutants, both Ptchd1_a and Ptchd1_c were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of Ptchd1 and Ptchd1 mice suggest a functional link between PTCHD1/Ptchd1 and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.
Hospital-treated infection associated with Alzheimer's disease pathology: underlying mechanisms.
Barichello T, Scaini G, Tayyab M … +3 more , Dal-Pizzol HR, Petronilho F, Dal-Pizzol F
Mol Psychiatry · 2026 Jun · PMID 42297936 · Publisher ↗
IMPORTANCE: Growing epidemiological and mechanistic evidence indicates that infections substantially increase the risk of Alzheimer's disease (AD) and related dementias. Systemic immune activation and pathogen persistenc...
IMPORTANCE: Growing epidemiological and mechanistic evidence indicates that infections substantially increase the risk of Alzheimer's disease (AD) and related dementias. Systemic immune activation and pathogen persistence may act as upstream triggers accelerating neurodegenerative cascades. OBJECTIVE: To synthesize recent evidence on infection-driven mechanisms contributing to AD pathology, emphasizing how systemic and central immune activation influence amyloid-beta (Aβ) aggregation, tau pathology, blood-brain barrier (BBB) dysfunction, and neuroinflammation. DESIGN, SETTING, AND PARTICIPANTS: This expert review integrates data from large epidemiological cohorts, neuropathological analyses, and mechanistic studies in both human and animal models to address innate and adaptive immune mechanisms linking infection to AD pathogenesis. EXPOSURES: Systemic and central nervous system (CNS) infections, including sepsis, pneumonia, viral, and chronic bacterial infections, as well as hospital-treated infections, that trigger inflammatory and immune signaling cascades impacting the brain's structural and molecular integrity. RESULTS: Infections activate the innate immune system through toll-like receptors and inflammasomes (NOD-like receptor family pyrin domain-containing 3 (NLRP3), linear ubiquitin assembly complex (LUBAC)), driving chronic neuroinflammation, pyroptosis, and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck that cross-seeds Aβ and tau aggregation. Additionally, cytokine-induced upregulation of interferon-induced transmembrane protein 3 (IFITM3) enhances γ-secretase activity, thereby increasing Aβ production. Therefore, peripheral inflammation compromises BBB integrity, while extracellular vesicles propagate inflammatory cargoes across the neurovascular unit. Consequently, the expansion of cytotoxic CD8⁺ T cells and the alteration of Th1/Th17 profiles are linked to adaptive immunity and neurodegeneration. Moreover, epidemiologic data show reduced AD risk following herpes zoster, Tdap/Td (tetanus, diphtheria, and acellular pertussis (Tdap) and tetanus and diphtheria (Td) vaccines), and pneumococcal vaccination, supporting immune modulation as a preventive strategy. CONCLUSIONS AND RELEVANCE: Infection-driven immune activation represents a key modifiable pathway in AD pathogenesis, highlighting novel diagnostic and therapeutic targets focused on the inflammasome.
Evidence supporting the role of GIGYF2 in synapse development and autism.
Yu B, Zhu S, Xiao L … +38 more , Chen G, Deng S, Wang Z, Zhuang R, Lyu Y, Tan S, Jia X, Liao X, Liao Y, Li X, Zhang G, Zhang Q, Jiang Y, Bai T, Zhu P, Shen L, Hoekzema K, Platzer K, Schnabel F, Jamra RA, Peeters H, Rondeau S, Rio M, Barcia G, Fisher R, Hannibal MC, Kesler OL, Robin NH, Thiffault I, Paolillo VK, Helbig J, Yuan L, Hu Z, Li J, Tan J, Eichler EE, Xia K, Guo H
Mol Psychiatry · 2026 Jun · PMID 42297935 · Publisher ↗
Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinica...
Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.
Distinct contributions of schizophrenia and neurotransmitter pathway genetic liability to neurocognition and antipsychotic efficacy in drug-naïve first-episode schizophrenia.
Yu T, Lu Z, Huang B … +13 more , Sun Y, Zhao G, Kang Z, Sun J, Guo J, Zhang X, Feng X, Zhu Y, Yuan R, Yu X, Pu C, Zhang Y, Yue W
Mol Psychiatry · 2026 Jun · PMID 42297934 · Publisher ↗
The genetic mechanisms underlying heterogeneity in symptom presentation and antipsychotic response in schizophrenia remain unclear, limiting the development of personalized treatment. We integrated genome-wide schizophre...
The genetic mechanisms underlying heterogeneity in symptom presentation and antipsychotic response in schizophrenia remain unclear, limiting the development of personalized treatment. We integrated genome-wide schizophrenia polygenic risk scores (SZ-PRS) and pathway-specific PRSs (pPRSs) for four major neurotransmitter systems to examine their associations with clinical phenotypes across the course of illness. Primary analyses were conducted in 394 drug-naïve, first-episode patients from the Chinese First-Episode Schizophrenia Trial (CNFEST) to investigate associations with baseline symptom severity, neurocognitive impairment, and longitudinal treatment response. The CNFEST cohort included 52-week longitudinal assessments of symptoms and neurocognition using the Positive and Negative Syndrome Scale and a modified version of the MATRICS Consensus Cognitive Battery. An independent case-control cohort evaluated associations with schizophrenia diagnosis, while a cohort of 514 healthy adults assessed whether PRS-cognition associations are specific to schizophrenia. Higher SZ-PRS predicted schizophrenia diagnosis (OR = 2.28, P = 0.003) and poorer baseline executive function (β = -0.44, P = 0.006) and working memory (β = -0.49, P = 0.018), but these associations were absent in healthy adults. In contrast, pPRSs showed weaker associations with diagnosis and baseline cognition but were more informative for treatment outcomes: higher serotonin-pPRS predicted greater improvement in depressive symptoms (P = 0.023-0.032), and higher GABA-pPRS predicted greater improvement in overall symptoms (P = 0.038-0.043) during weeks 4-24. Exploratory drug-specific analyses further suggested that treatment response varied across antipsychotics and was differentially associated with pPRSs. These findings demonstrate that genome-wide and pathway-specific PRSs contribute distinctly to schizophrenia phenotypes, supporting their integration for personalized stratification and treatment.
NTPDase2 suppresses hippocampal astrocyte-supplied cholesterol through hydrolyzing eATP in depression.
Zuo N, Liu SS, Pan SM … +6 more , Ou-Yang XP, Yao JS, Zhou YL, Zhou YF, Kong LD, Pan Y
Mol Psychiatry · 2026 Jun · PMID 42297933 · Publisher ↗
Depression is associated with cholesterol metabolism dysregulation, but the exact correlation and underlying mechanism remain unclear. Here, our finding reveals a notable reduction in cholesterol, specifically in apolipo...
Depression is associated with cholesterol metabolism dysregulation, but the exact correlation and underlying mechanism remain unclear. Here, our finding reveals a notable reduction in cholesterol, specifically in apolipoprotein E lipoprotein (ApoE-Lps)-carried cholesterol, in cerebrospinal fluid (CSF) of depressed rats exposing to chronic unpredictable mild stress (CUMS) or stress-level corticosterone. Consistently, Mendelian randomization (MR) analysis also showed that low level of total cholesterol in CSF may be as a risk factor associated with the characteristic symptom of depression such as anhedonia. More importantly, intracerebroventricular cholesterol administration alleviates changes in hippocampal neuronal morphology and depressive-like behaviors in CUMS rats. In astrocyte-neuron co-culture in vitro, astrocytic cholesterol release is decreased under corticosterone exposure. Mechanistically, increased nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) suppresses ATP-binding cassette G1 (ABCG1)-mediated cholesterol efflux by hydrolyzing extracellular ATP (eATP) in corticosterone-exposed astrocytes. Knockdown of Ntpdase2 in rat hippocampal astrocytes via adeno-associated virus (AAV) exhibits beneficial effects in increasing hippocampal neuronal cholesterol level, protecting neuronal morphology and improving depressive-like behaviors compared with vehicle-injected corticosterone model. Collectively, this study suggests impaired astrocytic cholesterol efflux as a cause of abnormality in hippocampal neuronal structure and identifies NTPDase2 as a potential therapeutic target for depression.
A novel composite model of PTSD induced by social bullying: validation via multidimensional behavioral and molecular biomarkers.
Liu X, Jia YL, Wang JY … +10 more , Yu SW, Cai CY, Li JX, Cheng D, Kang JH, Wu HT, Yuan TF, Liu F, Xu TL, Shen Y
Mol Psychiatry · 2026 Jun · PMID 42297932 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by persistent fear memory, hyperarousal, and social impairment. Mounting evidence highlights the critical role of social stress,...
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition characterized by persistent fear memory, hyperarousal, and social impairment. Mounting evidence highlights the critical role of social stress, such as bullying, in triggering PTSD. However, progress in elucidating the underlying mechanisms and developing effective treatments has been hindered by the lack of animal models that accurately recapitulate the multidimensional etiology of social trauma-related PTSD. To address this gap, we developed a novel triple-composite social bullying (SB) model in mice, which integrates social aggression, physiological pain, and psychological isolation to mimic the pathogenesis of PTSD induced by social bullying. Mice subjected to social bullying paradigm exhibited robust PTSD-like phenotypes, including anxiety- and depression-like behaviors, enhanced cue-induced fear responses, along with a prominent social avoidance phenotype that was not observed in the conventional foot shock (FS) model. Systemic administration of fluoxetine (10 mg/kg, intraperitoneal injection) significantly alleviated these behavioral deficits. Paralleled with these behavioral changes, neural hyperactivation in brain regions associated with fear and stress (anterior cingulate cortex [ACC], basolateral amygdala [BLA]), suppressed activity in the dorsal hippocampus (dHIP), reduced dendritic complexity in limbic areas, elevated expression of the FKBP51-glucocorticoid receptor (GR) complex, and increased cortisol levels. Collectively, this study demonstrates that the SB model faithfully recapitulates the core clinical manifestations of social trauma-induced PTSD across behavioral, neural, cellular, and molecular dimensions. The model thus provides a rigorously validated preclinical tool for investigating mechanisms of social trauma-related PTSD and screening potential therapeutic interventions.
Biobank-based genetic characterization of neurodegenerative diseases and idiopathic normal pressure hydrocephalus: insights and lessons learned from FinnGen.
Heikkinen S, Julkunen V, Martiskainen H … +6 more , Takalo M, Solje E, Leinonen V, Haapasalo A, Lipponen A, Hiltunen M
Mol Psychiatry · 2026 Jun · PMID 42286187 · Publisher ↗
Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have u...
Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by AD‑like pathological features. In this expert review, we summarize FinnGen‑based investigations relevant to neurodegenerative diseases and iNPH, highlighting insights into genetic susceptibility, disease overlap, and protective factors, and discuss how integration with recall studies as well as biomarker and clinical data accelerates translational applications in brain disorders.
Schizophrenia-associated glycoprotein Adamtsl3 regulates perineuronal net formation, maintenance, and adult cortical plasticity.
Cramer TML, Hannan SB, Petre L … +3 more , Bear MF, Hensch TK, Tyagarajan SK
Mol Psychiatry · 2026 Jun · PMID 42277231 · Publisher ↗
Perineuronal nets (PNNs) regulate the maturation of parvalbumin-positive (PV+) interneurons during postnatal critical periods and continue to support their function thereafter. Their disruption is implicated in neuropsyc...
Perineuronal nets (PNNs) regulate the maturation of parvalbumin-positive (PV+) interneurons during postnatal critical periods and continue to support their function thereafter. Their disruption is implicated in neuropsychiatric disorders such as schizophrenia, yet key endogenous PNN regulators remain unknown. Here, we identify the schizophrenia-associated glycoprotein Adamtsl3 as a PV+ cell-autonomous regulator of PNN integrity. Using mouse genetics, morphological and biochemical analyses, we demonstrate that Adamtsl3 deletion, both in early postnatal and adult stages, results in PNN deficits. Mechanistically, Adamtsl3 modulates matrix metalloprotease-9 (MMP9) activity, and Adamtsl3 deletion results in elevated MMP9 levels, PNN reduction, decreased Otx2 uptake, and heightened oxidative stress in PV+ cells. MMP9 hyperactivity and PNN reduction can be rescued by pharmacological inhibition of MMP9. Deletion of Adamtsl3 in PV+ interneurons revealed its cell-autonomous function in modulating PNN integrity. Notably, conditional Adamtsl3 deletion in adult PV+ cells reactivated juvenile-like ocular dominance plasticity. These results position Adamtsl3 as a persistent, PV+ specific PNN regulator with direct implications for the pathophysiology of schizophrenia.
Cannabinoid use generalizes stress responses: involvement of astrocyte plasticity and activation of matrix metalloproteinases in the nucleus accumbens core.
Hodebourg R, Duncan L, Dereschewitz E … +1 more , Kalivas P
Mol Psychiatry · 2026 Jun · PMID 42277230 · Publisher ↗
The rising legal acceptance of cannabis and the high comorbidity between cannabis use disorder (CUD) and post-traumatic stress disorder (PTSD) highlight the importance of understanding how stress and cannabis influence t...
The rising legal acceptance of cannabis and the high comorbidity between cannabis use disorder (CUD) and post-traumatic stress disorder (PTSD) highlight the importance of understanding how stress and cannabis influence the brain. We recently discovered that cannabinoid use promotes two PTSD-like symptoms: avoidance coping behaviors and the generalization of stress-coping responses to a neutral stimulus. Here, we used in vivo zymography and confocal microscopy to examine how stress and cannabinoid use influence multipartite synaptic plasticity. Specifically, we assessed astroglial plasticity, Synapsin-I density, and matrix metalloproteinases (MMP-2,9) activity, in the nucleus accumbens core (NAcore). For this purpose, rats were restrained for 2 h and simultaneously exposed to an odor; the stress-conditioned stimulus (stress-CS). Three weeks later, rats were exposed to cannabinoid vapor (delta9-tetrahydrocannabinol+cannabidiol; THC + CBD) for 5 days, self-administered THC + CBD (i.v.) for 10 days, followed by 10 days of abstinence. We then evaluated the effect of stress-CS or neutral odor (NS) on coping strategies in a defensive burying task. We found that THC + CBD generalized stress responses to the NS, associated with astrocyte retraction from synapses and a decrease in Synapsin-I density. THC + CBD pretreatment promoted avoidant coping during stress-CS exposure, activated MMP-2,9, re-associated astrocytes with synapses, increased Synapsin-I density, and caused astrocyte atrophy. By inhibiting MMP-2,9, we found that stress-CS-induced plasticity required MMP-2,9 activation. MMP-2 inhibition also restored active coping behaviors during stress-CS exposure. Surprisingly, these neuroadaptations only occurred in males. Overall, these findings suggest a potential role for MMPs and astrocytes in the changes produced by THC + CBD use in responding to a stress-CS.
Plasma proteomics of sleep traits reveals systemic immune-metabolic pathways and genetically prioritized proteins.
Chen H, Wang X, Chen W … +3 more , Xu C, Tan X, Cao Z
Mol Psychiatry · 2026 Jun · PMID 42277229 · Publisher ↗
The plasma proteomic signatures of sleep disturbance remain poorly characterized. Using data from 43,709 predominantly European-ancestry, middle-aged and older UK Biobank participants, we depict a large-scale atlas of pl...
The plasma proteomic signatures of sleep disturbance remain poorly characterized. Using data from 43,709 predominantly European-ancestry, middle-aged and older UK Biobank participants, we depict a large-scale atlas of plasma proteomic signatures of seven self-reported sleep traits (sleep duration, chronotype, insomnia symptoms, daytime napping, daytime sleepiness, snoring, and ease of getting up in the morning) and a derived sleep health score. We identify 935 proteins associated with at least one sleep trait, converging on lipid metabolism, immune function and inflammation, cell adhesion, and neurochemical signaling. Leveraging genomic structural equation modeling to define three latent sleep factors, namely circadian preference, daytime sleep burden, and nighttime sleep adequacy, bidirectional Mendelian randomization (MR) identifies one protein (LTA) with robust cis-instrument and strong colocalization support (PP.H4 = 0.98) for a putative causal effect on nighttime sleep adequacy. Sixteen additional genetically supported candidate proteins rely primarily on trans-pQTL instruments or weaker colocalization. These genetically supported candidates are prospectively associated with incident cardiovascular disease, stroke, type 2 diabetes, dementia, chronic kidney disease, depression, and mortality over a median 13.6-year follow-up, with the strongest per-SD hazard ratio (HR) associations observed for chronic kidney disease (e.g., BTN2A1: HR = 2.33) and type 2 diabetes (e.g., RBP5: HR = 1.58). Collectively, these findings highlight the potential of large-scale proteomics in elucidating sleep pathogenesis, and generate testable hypotheses for validation in independent cohorts and experimental models.
GluD1 is localized at cholinergic synapses and is an acetylcholine receptor.
Chettiar PB, S Narasimhan KK, Sabnis SS … +4 more , Ericksen SS, Choi D, Smith Y, Dravid SM
Mol Psychiatry · 2026 Jun · PMID 42270762 · Publisher ↗
The GluD1 receptor has many unusual features including expression at both excitatory and inhibitory synapses and a ligand binding domain capable of binding both D-serine and GABA. We have previously demonstrated that str...
The GluD1 receptor has many unusual features including expression at both excitatory and inhibitory synapses and a ligand binding domain capable of binding both D-serine and GABA. We have previously demonstrated that striatal GluD1 is critical for the regulation of behavioral flexibility, a phenotype dependent on the cholinergic system. Here, we found that GluD1 is enriched postsynaptically at cholinergic synapses in the mouse and monkey dorsal striatum. Further, loss of GluD1 reduces the abundance of cholinergic terminals, excitatory responses at cholinergic synapses as well as muscarinic receptor-induced plasticity. In addition, optogenetic stimulation of cholinergic interneurons or puff-application of ACh, in the presence of cholinergic and AMPA/GABA receptor blockers, produced current responses in medium spiny neurons (MSNs) that were sensitive to the GluD1-channel blocker NASPM. These responses were absent in GluD1 KO and overexpression of GluD1 on KO background rescued Ach puff-induced currents suggesting potential conductance via GluD1. Finally, using GluD1-Cbln1 interaction assay as an indirect method to evaluate ligand binding interaction, we found that ACh can bind GluD1 and induce conformational changes. A similar ACh-induced conformational change was observed for GluD2 in the cell binding assay. Importantly, molecular dynamics simulations and mutagenesis analysis demonstrated that ACh binding orientation in the GluD1 ligand binding domain is different from D-serine and GABA. Overall, our results identified an unprecedented feature of GluD1 in the regulation of cholinergic synapses.
Differential DNA methylation in blood as potential mediator of the association between ambient PM and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.
Ma T, Liu J, Liang D … +7 more , Ebelt S, Steenland K, Levey AI, Lah JJ, Wingo AP, Wingo TS, Hüls A
Mol Psychiatry · 2026 Jun · PMID 42270761 · Publisher ↗
Fine particulate matter (PM) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While...
Fine particulate matter (PM) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF Aβ concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM exposure for the year preceding participants' blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM and decreased CSF Aβ concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from -0.015--0.029 per 1 ug/m increase in PM exposure. The proportion mediated ranging from 14-43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM exposure and CSF Aβ concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM toxicity in the pre-clinical stages of AD.
Anxiety influences the addictive feature of non-suicidal self-injury behavior via somatic symptom in adolescents with major depressive disorder.
Liu X, Yuan S, Zhang W … +6 more , Cheng F, Li G, Chen L, Tang Y, Song Q, Zhou D
Mol Psychiatry · 2026 Jun · PMID 42265226 · Publisher ↗
Adolescents with major depressive disorder (MDD) frequently engage in repetitive non-suicidal self-injury (NSSI), with a subset developing addictive patterns; however, the underlying mechanisms remain unclear. In this pr...
Adolescents with major depressive disorder (MDD) frequently engage in repetitive non-suicidal self-injury (NSSI), with a subset developing addictive patterns; however, the underlying mechanisms remain unclear. In this present study, 363 hospitalized adolescents with MDD and NSSI were assessed using graphical Gaussian and Bayesian networks to explore relationships among clinical symptoms, impulsivity, and the addictive feature of NSSI. The results revealed an anxiety-somatic-addictive NSSI pathway (anxiety-somatic: 1.00/0.79, edge strength/ directionality; somatic-addictive NSSI: 0.82/0.84) and identified motor impulsivity as an independent predictor (0.80/0.57). To further validate this pathway, a clinical trial was conducted in 58 adolescents with MDD and NSSI receiving accelerated intermittent theta-burst stimulation (a-iTBS) targeting the left dorsolateral prefrontal cortex. Participants were stratified into high- and low-response groups, and mediation analyses were performed. At baseline, anxiety exerted a significant indirect effect on addictive NSSI via somatic symptom in both groups (high-response: β = 0.51,95% CI = [0.15, 1.19]; low-response: β = 0.24, 95% CI = [0.07, 0.45]), indicating a fully mediated pathway. Notably, this mediation effect was no longer significant following intervention (high-response: β = -0.02, 95% CI = [-0.17, 0.19]; low-response: β = 0.09, 95% CI = [-0.05, 0.30]). However, in the low-response group, regression analyses further confirmed somatic symptom as a predictor of NSSI addictive feature (β = 0.18, 95% CI = [0.03, 0.34]). These findings suggest that anxiety drives the addictive feature of NSSI via somatic symptom in MDD adolescents with repetitive NSSI. A-iTBS is a positive intervention for addictive NSSI.
Hierarchical neural variability reveals adaptive and maladaptive mechanisms of non-suicidal self-injury.
Li J, Xie Y, Ni F … +5 more , Tang E, Xu Z, Wu Z, Wu S, Wang C
Mol Psychiatry · 2026 Jun · PMID 42249070 · Publisher ↗
Non-suicidal self-injury (NSSI) is a prevalent and clinically urgent condition in adolescence, marked by impairments in cognitive flexibility-a capacity thought to be supported by neural variability. However, most resear...
Non-suicidal self-injury (NSSI) is a prevalent and clinically urgent condition in adolescence, marked by impairments in cognitive flexibility-a capacity thought to be supported by neural variability. However, most research to date has focused on static brain features, leaving the role of variability largely unexplored. Importantly, variability-based metrics have been emerging as promising biomarkers in psychiatry, offering superior test-retest and intersession reliability compared with traditional static metrics. Leveraging resting-state fMRI data from 160 psychiatric patients with NSSI, primarily diagnosed with major depressive disorder, bipolar disorder, or borderline personality disorder, and 50 psychiatric controls without a history of NSSI, primarily diagnosed with major depressive disorder or bipolar disorder, we examined neural variability at two hierarchical levels-connectivity and network topology-and evaluated their clinical relevance using cross-sectional and longitudinal data. Patients with NSSI consistently exhibited heightened variability at both the connectivity and topology levels, and these measures demonstrated moderate discriminative value in classifying NSSI from psychiatric controls. The functional implications, however, diverged between two levels. Greater connectivity-level variability was associated with better emotional and attentional functioning at baseline, and larger reductions in NSSI behaviors over three months. In contrast, greater topology-level variability was linked to higher impulsivity, and poorer behavioral improvement. These findings reveal that elevated neural variability in NSSI encompass both adaptive and dysregulated dynamics: increases in connectivity variability may promote flexible adaptation, serving as compensatory functions, whereas excessive large-scale reconfiguration in topology may indicate loss of global control, reflecting maladaptive mechanisms. Parallel analyses on conventional static brain features confirmed the complementary role of neural variability. Together, our findings indicate that disruptions in variability across two hierarchies may constitute a neural mechanism underlying NSSI and highlight neural variability as a potential prognostic marker.
Efficacy of pharmacological and microbiota-based therapies in preclinical models of autism spectrum disorder: a systematic review.
Kunevičius A, Gawlińska K, Burokas A … +1 more , Gawliński D
Mol Psychiatry · 2026 Jun · PMID 42243298 · Publisher ↗
BACKGROUND: Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition in which pharmacological and microbiota-targeted interventions are emerging as promising therapeutic avenues. Animal models are...
BACKGROUND: Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition in which pharmacological and microbiota-targeted interventions are emerging as promising therapeutic avenues. Animal models are the main tool to investigate etiology, molecular mechanisms and screening for pharmacological therapies. Methodological differences, outcome measure variability, incomplete reporting, biological confounders, and overgeneralization of the results made evaluating innovative pharmacological agents challenging. These limitations in the field highlight a need for systematic and standardized research to reliably assess and translate pharmacological interventions from ASD animal models to human clinical relevance. SUBJECTS: This systematic review synthesized efficacy evidence for pharmacological and microbiota-based therapies across established ASD animal models. RESULTS: We identified 52 recent (2010-2025) studies that reported key ASD behavioral outcomes after pharmacological or microbiota-focused treatments. Interventions were grouped into therapeutic classes - including oxytocinergic agents, E/I balance therapeutic targets, metabolic drugs, cannabinoids, purine-based interventions and emerging targets - alongside microbiota-directed strategies such as probiotics, prebiotics, and fecal microbiota transplantation. By integrating effect directions and robustness across models, we identified most potential drug candidates, evaluated the efficacy of novel strategies, and recognized critical translational gaps. The reviewed studies demonstrate that ASD-like behavioral deficits in preclinical models can be modulated through interventions targeting diverse biological systems, including neurotransmission, neuroinflammation, metabolism, and the gut-brain axis. CONCLUSIONS: These findings support the multifactorial nature of ASD pathophysiology which arises from a network of interacting systemic processes rather than a single molecular defect. It could explain the limited success of traditionally narrowly targeted interventions and suggest a paradigm shift into a more systemic approach.
NgR-Dependent plasticity in a dCA3 → VTA → NAc circuit underlies stress resilience and susceptibility.
Zhao J, Lian H, Wang B … +7 more , Zhang D, Gong S, Cao Z, Ma G, Shang L, Sun H, Jiang R
Mol Psychiatry · 2026 Jun · PMID 42243297 · Publisher ↗
The Nogo receptor (NgR), a core receptor for myelin-derived axon growth inhibitors, has been implicated not only in the regulation of synaptic plasticity but also in the pathogenesis of various neuropsychiatric disorders...
The Nogo receptor (NgR), a core receptor for myelin-derived axon growth inhibitors, has been implicated not only in the regulation of synaptic plasticity but also in the pathogenesis of various neuropsychiatric disorders. However, its specific role and the underlying circuit mechanisms in the development of depression remain elusive. This study used a chronic unpredictable mild stress (CUMS) model in male mice and found that the expression of the NgR in the dorsal CA3 (dCA3) region of the hippocampus was significantly increased in depressive-like mice, and it was mainly enriched in glutamatergic neurons with reduced excitability. Downregulation of NgR in dCA3 or enhancement of glutamatergic neuronal excitability significantly alleviated depressive-like behaviors, while upregulation of NgR or inhibition of glutamatergic neuronal excitability promoted stress-induced depressive-like behaviors. Notably, dCA3 glutamatergic neurons specifically project to the dopaminergic neuronal pathway in the ventral tegmental area (VTA) and its downstream dopaminergic projections to the nucleus accumbens (NAc). The inhibition of D1/D2 receptors in the NAc is required for mediating depressive-like behaviors. Furthermore, downregulation of NgR in dCA3 exerts antidepressant-like effects by disinhibiting the neurons projecting to the VTA → NAc pathway. This study systematically reveals the role of NgR in dCA3 glutamatergic neurons and the dCA3 → VTA → NAc circuit in depressive-like behaviors, providing a new theoretical basis for developing potential therapeutic strategies targeting myelin-related signaling pathways for depression.
Alcohol abstinence precipitates alcohol seeking and aversion-resistant intake in association with increased BNST activity.
Doyle MA, Yoon HJ, Altemus ME … +11 more , Park AS, Troutman ME, Grunenkovaite L, Adank DN, Edwards CM, Chetkovich NA, Hallal SD, Lantier L, Siciliano CA, Calipari ES, Winder DG
Mol Psychiatry · 2026 Jun · PMID 42237002 · Publisher ↗
Alcohol Use Disorder (AUD) is defined by a common diagnostic framework, yet individuals show diverse drinking patterns and relapse vulnerabilities during abstinence, reflecting neurobiological heterogeneity. The bed nucl...
Alcohol Use Disorder (AUD) is defined by a common diagnostic framework, yet individuals show diverse drinking patterns and relapse vulnerabilities during abstinence, reflecting neurobiological heterogeneity. The bed nucleus of the stria terminalis (BNST) is well positioned to contribute to this variability. To understand how BNST activity co-segregates with individual alcohol behavior trajectories, we used the Structured Tracking of Alcohol Reinforcement (STAR) operant task to phenotype C57BL/6J mice as high, low, or aversion-resistant ethanol drinkers. During initial self-administration, dBNST cFos+ counts correlated with intake, linking dBNST activation to operant drinking. Using in vivo fiber photometry, we found that aversion-resistant drinkers displayed elevated dBNST calcium transients during drinking bouts despite similar intake across groups, consistent with heightened dBNST recruitment. Forced abstinence uncovered prominent phenotype-specific adaptations, where ethanol seeking during protracted, but not early, abstinence predicted aversion-resistant intake. High and low drinkers reduced seeking behavior across abstinence, whereas aversion-resistant drinkers persisted. Consistently, dBNST calcium transients increased during protracted abstinence seeking only in aversion-resistant drinkers, highlighting phenotype-specific plasticity. Comparing mice exposed to abstinence versus only operant training showed that abstinence itself potentiates aversion-resistant intake. Finally, these dBNST dynamics were ethanol-specific, as saccharin drinking more closely reflected activity for high drinkers. Together, these findings reveal that ethanol abstinence precipitates ethanol seeking and aversion-resistant intake, associated with phenotypic dBNST calcium dynamics. Because causality was not established, future studies are needed to define mechanistic contributions of dBNST activity to phenotypic behaviors. By uncovering how dBNST activity adapts in aversion-resistant drinkers, this work offers insight into AUD heterogeneity.
Genetics of major depressive disorder in a homogeneous population with uniform phenotyping.
Huider F, Milaneschi Y, Pool R … +28 more , Maciel BAPC, Gordon SD, Han J, Rietman ML, Kok AAL, Galesloot TE, Mitchell BL, 't Hart LM, Rutters F, Blom MT, Rhebergen D, Visser M, Brouwer IA, Feskens E, Hartman CA, Oldehinkel AJ, Bot M, de Geus EJC, Kiemeney LA, Huisman M, Picavet HSJ, Verschuren WMM, Martin NG, Dolan CV, van Loo HM, Penninx BWJH, Hottenga JJ, Boomsma DI
Mol Psychiatry · 2026 Jun · PMID 42230966 · Publisher ↗
Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major d...
Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (r = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD.
Sex-specific regulation of angiogenin in Alzheimer's disease.
Jörg M, Walz L, Nathal S … +10 more , Kristen M, Lietz C, Müller M, Nguyen VTT, Ruffini N, Winz ML, Gerber S, Endres K, Helm M, Friedland K
Mol Psychiatry · 2026 Jun · PMID 42230965 · Publisher ↗
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease...
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder, highlighting the need to identify novel molecular regulators for effective treatment development. Angiogenin (ANG), a stress-responsive ribonuclease that inhibits apoptosis by generating 5'-tRNA fragments, is a candidate whose expression and regulation in AD is not understood. Here, we investigated ANG expression and regulation using AD cell and animal models, postmortem human brain tissue, and transcriptomic datasets (n = 645). We found that ANG is dysregulated in AD in a sex-dependent manner, altering downstream levels of 5'-tiRNA. Our analysis revealed female-specific molecular subtypes, absent in males: Subtype 1 featured low ANG levels with increased inflammation and neuronal death; subtype 2 exhibited higher ANG expression and intermediate pathology; subtype 3, marked by the highest ANG levels, showed reduced inflammation, slower cognitive decline, and extended survival. These findings position ANG as a key modulator of neuroinflammation and apoptosis in AD, highlighting its potential as a treatment strategy.
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