Molecular Psychiatry[JOURNAL]
Sun
200 papers
Rapid rescue of despair behaviors by sonogenetic neuromodulation of the mPFC-DRN pathway.
Lei T, Xian Q, Li D … +11 more , Su M, Wu Y, Hou X, Jing J, Jiang Y, Huang X, Wong KF, Zhu J, Guo J, Qiu Z, Sun L
Mol Psychiatry · 2026 Apr · PMID 41998192 · Publisher ↗
Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics'...
Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics' potential in a mouse depression model, targeting excitatory medial prefrontal cortex (mPFC) neurons projecting to the dorsal raphe nucleus (DRN). Projecting neurons were induced to express a mechanosensitive ion channel (MscL-G22S), and alterations in patterns of neuronal activation and despair-like behaviors upon sonication were evaluated. Sonogenetics selectively activated targeted excitatory mPFC neurons projecting to the DRN, enhancing real-time DRN neuronal activity and serotonin release, with no observed tissue damage or astrocytic/microglial activation. Tail suspension and forced swim tests revealed that sonogenetically activating this pathway rapidly reversed despair-like behaviors in stressed mice, whereas effects observed upon mPFC sonication were abrogated by functionally silencing downstream DRN neurons, and this effect is fully recapitulated by selective inhibition of DRN serotonergic neurons alone. Collectively, this study constitutes the first demonstration of the potential for a circuit-targeted sonogenetic therapeutic approach for relieving despair behaviors.
Ceruloplasmin deficiency drives a fusiform-centric lipid-myelin pathology underlying a visual subtype in autism.
Deng YY, Zhong SS, Wang SH … +12 more , Yin BY, Zhou X, Zou FY, Zhao JY, Ni YX, Luo XW, Shen LS, Zhang JL, Lin ZP, Zhou WY, Deng HZ, Guo RM
Mol Psychiatry · 2026 Apr · PMID 41998191 · Publisher ↗
Atypical visual processing (AVP) commonly occurs in autism spectrum disorder (ASD) and contributes to social impairments, yet its neurobiological basis remains poorly characterized. To investigate potential lipid and mye...
Atypical visual processing (AVP) commonly occurs in autism spectrum disorder (ASD) and contributes to social impairments, yet its neurobiological basis remains poorly characterized. To investigate potential lipid and myelin mechanisms, this study integrated multimodal MRI, quantifying lipid (proton density fat fraction) and myelin content (synthetic MRI) of 74 nuclei or brain regions, with serum profiling of iron, lead, and ceruloplasmin in 288 children, including 90 ASD with atypical visual processing (ASD‑AVP), 89 ASD without atypical visual processing (ASD‑AVP), and 109 typically developing (TD). The ASD-AVP subgroup exhibited a distinct co-pathology of elevated lipid and myelin centered on the fusiform gyrus (FG), accompanied by a unique positive lipid-myelin correlation (left: r = 0.47, right: r = 0.41). Serum analyses revealed decreased iron and ceruloplasmin and increased lead in ASD-AVP, and mediation analysis indicated that ceruloplasmin deficiency influences FG myelination via lipid pathways (35%-55%). Crucially, BTBR AVP-like mice recapitulated this phenotype with disorganized hypermyelination, whereas nAVP-like mice showed hypomyelination. A combined FG lipid-myelin signature strongly distinguished ASD-AVP from TD (AUC = 0.93) and ASD-nAVP (AUC = 0.87). Preliminary longitudinal follow-up in a subset of patients revealed that improvement in serum ceruloplasmin was associated with a reduction in FG lipid content and stabilization of myelin, paralleling clinical improvement. These findings identify a ceruloplasmin-driven, FG-centric lipid-myelin co-pathology, representing a maladaptive "inflammatory pseudo-compensation" mechanism specific to a visual ASD subtype, and offer novel biomarkers for biological subtyping and targeted interventions.
Sterol pathway disruption in pregnancy: a link to autism.
Peeples ES, Anzalone AJ, Dai R … +3 more , Reisher E, Korade Z, Mirnics K
Mol Psychiatry · 2026 Apr · PMID 41991716 · Publisher ↗
Cholesterol is a vital molecule, especially during embryonic development. Disruption of the cholesterol biosynthetic pathway can arise from pathogenic genetic variants or exposure to prescription medications. We investig...
Cholesterol is a vital molecule, especially during embryonic development. Disruption of the cholesterol biosynthetic pathway can arise from pathogenic genetic variants or exposure to prescription medications. We investigated the relationship between fifteen sterol biosynthesis inhibiting medications (SBIM) prescribed during pregnancy and the incidence of autism spectrum disorders (ASD) in the resulting offspring. Our study of the Epic Cosmos database queried linked child and maternal health records for births between 2014 and 2023 with follow-up to December 2025. The study included 6,135,213 children with linked maternal health records. We evaluated the incidence of ASD associated with maternal prescription of aripiprazole, atorvastatin, bupropion, buspirone, fluoxetine, haloperidol, metoprolol, nebivolol, pravastatin, propranolol, rosuvastatin, sertraline, simvastatin, and/or trazodone during pregnancy using Cox proportional hazard modeling. We found that exposure to at least one SBIM during pregnancy was associated with a 1.47-fold (95% CI 1.45-1.49) increased risk of an ASD after adjusting for potential confounders. For each additional SBIM co-prescribed, there was a 1.33 (95% CI 1.32-1.34) times increased risk of ASD, reaching 2.33-fold risk when 4 or more SBIMs were prescribed simultaneously. In the ten years of our cohort, we identified 234,971 (3.8%) children with an ASD diagnosis. Of the children with an ASD diagnosis, 35,152 (15.0%) of the mothers were prescribed at least one SBIM during pregnancy. Notably, in our dataset, utilization of SBIM medications by pregnant women increased from 4.6% in 2014 to16.8% in 2023. In conclusion, SBIMs may be potentially harmful to the developing fetus. Given that these drugs account for over 400 million prescriptions annually in the U.S. we recommend these findings be considered before prescribing SBIM medications during pregnancy.
Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.
Wei P, Zhu T, Hashimoto K … +2 more , Jia M, Yang JJ
Mol Psychiatry · 2026 Apr · PMID 41991715 · Publisher ↗
Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, t...
Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.
Ethanolamine as a potential biomarker and therapeutic target for depressive disorder.
Ogawa S, Hattori K, Hidese S … +24 more , Sasayama D, Ota M, Miyakawa T, Tatsumi M, Matsumura R, Yoshida S, Noda T, Takebayashi M, Omori W, Itagaki K, Kajitani N, Okada-Tsuchioka M, Hishimoto A, Boku S, Horai T, Monji A, Mizoguchi Y, Tateishi H, Murakawa-Hirachi T, Yoshimura R, Igata R, Kim Y, Hori H, Kunugi H
Mol Psychiatry · 2026 Apr · PMID 41986746 · Publisher ↗
We investigated cerebrospinal fluid (CSF) ethanolamine (EA) levels in major depressive disorder (MDD), to validate our previous findings on EA (Ogawa et al., 2015) and broaden its biological context and translational rel...
We investigated cerebrospinal fluid (CSF) ethanolamine (EA) levels in major depressive disorder (MDD), to validate our previous findings on EA (Ogawa et al., 2015) and broaden its biological context and translational relevance. Using human samples (sets A-C) and animal models, we explored the implications for replication, translational potential, therapeutic development, and mechanistic insight. In set A (n = 380), CSF EA levels were low in patients with MDD (P = 0.00047, Cohen's d = -0.59), negatively correlating with depression severity (Spearman's ρ = -0.29, P = 0.00015) and positively correlating with CSF homovanillic acid (partial r = 0.40, P = 6.7E - 8) and 5-hydroxyindoleacetic acid levels (partial r = 0.26, P = 0.00064). Patients with moderate-to-severe depression showed large effects regardless of medication (Cohen's d = -1.27 to -1.14). In set B (n = 13), CSF EA levels were significantly increased in patients who received electroconvulsive therapy (P = 0.0071; Cohen's d = 0.90), which was linked to Hamilton Depression Rating Scale subscale score recovery. In set C (n = 66), a novel multicenter-collected sample set, CSF EA levels were low in patients with MDD (P = 0.0037; Cohen's d = -0.91). Rats receiving 0.5 or 1.0 mg/kg lipopolysaccharide intraperitoneally for 7 days showed significantly reduced CSF EA levels (P = 0.014; Cohen's d = -1.52 and 0.00020; d = 2.31, respectively) and depressive-, anxiety-, and anhedonia-like behaviors. Rats orally administered EA for 4 weeks showed significant antidepressant-like behaviors (P = 0.016; Cohen's d = -1.36). Proteomic and bioinformatic analyses revealed 40 proteins that were significantly correlated with CSF EA levels. The top hit protein was CHL1 (partial r = 0.42, P = 1.5E - 9), and the axon guidance pathway was the most enriched (P = 3.4E - 20). EA is a potential CSF biomarker for mental state evaluation, treatment response, subtyping, and validation of MDD animal models and a promising research tool for developing a new classification framework for psychiatric disorders and novel therapeutic strategies.
Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered Na channel dynamics in human neurons.
Cui L, Kurganov E, Hawes D … +7 more , Hornauer P, Lin R, Wang Y, Hierlemann A, Sheng M, Nehme R, Pan JQ
Mol Psychiatry · 2026 Apr · PMID 41986745 · Publisher ↗
Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional con...
Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Na1.2, a voltage-gated sodium channel encoded by SCN2A, which displays aberrant subcellular distribution in XPO7 LoF neurons. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.
Genome-wide tandem repeat expansions modify schizophrenia risk in the presence of a 22q11.2 deletion.
Cheng M, Yin Y, Engchuan W … +5 more , Heung T, International 22q11.2 Brain Behavior Consortium (IBBC), Morrow BE, Bassett AS, Yuen RKC
Mol Psychiatry · 2026 Apr · PMID 41986744 · Publisher ↗
Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood....
Schizophrenia develops in one in every four individuals with a pathogenic 22q11.2 deletion, yet the genetic modifiers influencing the manifestation of schizophrenia in this high-risk group remain incompletely understood. Here, we identify rare tandem repeat expansions (TREs) as significant contributors to schizophrenia risk in this population. Genome sequencing of 438 unrelated individuals with 22q11.2 deletions revealed a marked enrichment of rare genic TREs among those with schizophrenia, with effect sizes comparable to common polygenic risk. These TREs are disproportionately located in intronic and splice-adjacent regions relative to other genomic regions, with evidence suggesting that they disrupt gene regulation through mechanisms including altered methylation and splicing. Cell-type-specific analyses indicate that TREs are primarily associated with differentially expressed genes in excitatory and inhibitory neurons in the prefrontal cortex. Affected genes, including DLGAP2 and DMPK, are involved in neurodevelopment and synaptic organization. These findings extend the role of TREs as genetic modifiers, providing new insights into the molecular mechanisms underlying schizophrenia in this ultra-high-risk population and into the broader biology of idiopathic schizophrenia.
Accelerated intermittent theta burst stimulation targeting personalized fronto-parietal control network improves core symptoms of autism spectrum disorder: a double-blind, randomized controlled trial.
Liu Q, Zhang J, Duan X … +17 more , Zhang P, Yang Y, Yao G, Jiaerheng B, Shou XJ, He Y, Han K, Jia M, Wang L, Gong W, Xie W, Sun K, Wang D, Wu XD, Cao H, Zhang H, Liu H
Mol Psychiatry · 2026 Apr · PMID 41986743 · Publisher ↗
Autism Spectrum Disorder (ASD) presents a substantial global challenge, yet no pharmacological treatments effectively target its core symptoms, especially in individuals with severe cognitive or adaptive impairments. Thi...
Autism Spectrum Disorder (ASD) presents a substantial global challenge, yet no pharmacological treatments effectively target its core symptoms, especially in individuals with severe cognitive or adaptive impairments. This double-blind, sham-controlled, randomized clinical trial assessed accelerated intermittent theta burst stimulation (iTBS) targeting the personalized fronto-parietal network (FPN) in ASD. Participants (6-30 years) were randomized in a 2:1 ratio to active or sham iTBS (three daily sessions, 1800 pulses/session) over 12 weeks (324k pulses) alongside behavioral training. The primary outcome was defined as the response rate, charaterized by a ≥ 1-point reduction in ADOS-2 SA at week 12. Of 132 individuals screened, 67 were randomized (mean age 10.04 ± 4.22 years; 88.1% male; all with cognitive/adaptive delays), with 59 completing the study. Active iTBS resulted in a significantly higher response rate (55% vs. 29%) and higher symptom improvement than sham (cohen's d = -0.53), with mild local pain in only 5% of iTBS group. In the profound autism subgroup, the active group exhibited language improvement alongside amelioration of core symptoms. These findings suggest that prolonged, accelerated FPN-targeted iTBS is a safe and efficacious intervention for severe ASD, offering a promising therapeutic approach.Registration ClinicalTrials.gov Identifier: NCT05890846.
Postpartum psychosis is associated with elevated neuromelanin-MRI signal in the midbrain.
McKenna F, Vinke LN, Williams M … +5 more , Gaw M, Dunk M, Jacobs H, Cohen L, Holt DJ
Mol Psychiatry · 2026 Jun · PMID 41986742 · Full text
OBJECTIVE: Postpartum psychosis (PP) is an uncommon psychiatric condition that, if untreated, can have devastating consequences. The underlying biology of PP remains poorly understood. To investigate the neurobiological...
OBJECTIVE: Postpartum psychosis (PP) is an uncommon psychiatric condition that, if untreated, can have devastating consequences. The underlying biology of PP remains poorly understood. To investigate the neurobiological mechanisms of PP, this study measured neuromelanin (NM)-sensitive magnetic resonance imaging (MRI) signal intensity, a marker of dopamine turnover, in the midbrain of women with a prior history of PP (n = 30) and a group of demographically-matched healthy control (HC) women (n = 24). METHODS: NM-MRI signal intensity in dopamine-rich midbrain areas, the substantia nigra (SN) and ventral tegmentum area (VTA), as well as whole-brain resting-state functional connectivity of the bilateral SN, were measured and compared across the two groups. RESULTS: Significantly elevated levels of NM-MRI signal in the SN and VTA were observed in the PP (vs. the HC) group, and these elevations were significantly correlated with levels of residual, subclinical psychotic symptoms within the PP group. Additionally, significant decreases were observed in the PP (vs HC) group in the functional connectivity of the bilateral SN to multiple subcortical regions; these decreases were associated with levels of SN NM-MRI signal and subclinical psychotic symptoms. CONCLUSIONS: This study provides the first evidence for elevated midbrain NM-MRI signal in women with a history of PP. Also, this abnormality was linked to the presence of residual subclinical psychotic symptoms and altered connectivity of the SN. Future studies will determine whether NM-MRI can serve as a useful tool for screening women for risk for PP.
What are the correlates of non-suicidal self-injury in children and adolescents? An umbrella systematic review of global evidence.
Zhong Y, Zhang ZW, Ding JH … +19 more , Sun YK, Zheng YB, Yu YF, Guan ZC, Su SZ, Wu TT, Gong YM, Mi WF, Yan W, Sun J, Wang YM, Yuan K, Shi L, Wang Z, Javed A, Liu XX, Bao YP, Wasserman D, Lu L
Mol Psychiatry · 2026 Apr · PMID 41981212 · Publisher ↗
BACKGROUND: Non-suicidal self-injury (NSSI) persists as a major public health challenge worldwide. Identifying and strategically targeting risk factors for NSSI constitutes a practical approach to its prevention. We aim...
BACKGROUND: Non-suicidal self-injury (NSSI) persists as a major public health challenge worldwide. Identifying and strategically targeting risk factors for NSSI constitutes a practical approach to its prevention. We aim to synthesize existing knowledge concerning the range and magnitude of risk factors for NSSI among children and adolescents, and to critically assess the robustness of the available evidence. METHODS: In this umbrella review, six bibliographic databases were systematically searched for articles published from database inception to Dec 2024. For the assessment of evidence credibility, pre-specified criteria for classifying evidence were utilized, categorized as convincing ("class I"), highly suggestive ("class II"), suggestive ("class III"), weak ("class IV"), or no evidence ("class V"). The Amstar-2 framework was employed to evaluate the quality of the evidence which graded as "high," "moderate," "low," or "critically low" quality. RESULTS: The study included meta-analyses of observational studies in the past 30 years on risk factors for NSSI in children and adolescents. We identified 16 meta-analyses comprising 410 primary studies on 43 risk factors from 38 countries, involving 2,659,156 children and adolescents. Twenty-three (e.g. LGBTIQ) risk factors were categorized as individual, followed by family level (n = 8, e.g. childhood maltreatment), school/peer level (n = 8, e.g. bully victims) and multifactorial level (n = 4, e.g. no religion). Eighteen (41.86%) risk factors provided highly suggestive (Class II) evidence of association with NSSI. Suggestive evidence (class III) indicated that NSSI was associated with adverse childhood experiences (2.31, 1.77-3.01) and being left-behind children (1.37, 1.11-1.69). CONCLUSION: A multitude of risk factors spanning diverse domains were identified, highlighting the multifactorial nature of NSSI in adolescents and children. Comprehensive prevention strategies and measures should be conducted for children and adolescents to decrease the risk of NSSI and associated harms in multilevel approaches.
Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.
Zhu TT, Liu PM, Hashimoto K … +1 more , Yang JJ
Mol Psychiatry · 2026 Apr · PMID 41981211 · Publisher ↗
Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy....
Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.
Response to: "Re-examining interneuron-specific Nrp2 deletion: overlooked striatal and cortical contributions".
Subramanian D, Eisenberg C, Huang A … +6 more , Baek J, Naveed H, Komatireddy S, Shiflett MW, Tran TS, Santhakumar V
Mol Psychiatry · 2026 Apr · PMID 41974886 · Publisher ↗
This "Correspondence" is a "Response" to the "Comment" by Dr. Aihua Yuan and Dr. Bo Yuan, titled "Re-examining interneuron-specific Nrp2 deletion: overlooked striatal and cortical contributions", in relation to our publi...
This "Correspondence" is a "Response" to the "Comment" by Dr. Aihua Yuan and Dr. Bo Yuan, titled "Re-examining interneuron-specific Nrp2 deletion: overlooked striatal and cortical contributions", in relation to our published article "Dysregulation of neuropilin-2 expression in inhibitory neurons impairs hippocampal circuit development and enhances risk for autism-related behaviors and seizures". While the limitations expressed in the comment by Drs Yuan and Yuan regarding the potential extrahippocampal contributions to the behavioral deficits in mice with interneuron-specific Neuropilin 2 deletion are valid, we would like to emphasize that these issues were extensively and were thoroughly discussed in our publication and not overlooked.
Microglia respond to and induce anxiety and grooming in mice using calcium signaling.
Nagarajan N, Capecchi MR
Mol Psychiatry · 2026 Apr · PMID 41974885 · Publisher ↗
Disruption of the mouse Hoxb8 gene causes chronic anxiety and pathological over-grooming resulting from defective Hoxb8 microglia. Furthermore, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain...
Disruption of the mouse Hoxb8 gene causes chronic anxiety and pathological over-grooming resulting from defective Hoxb8 microglia. Furthermore, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety and/or grooming. Herein we show that the molecular signals for inducing anxiety and/or grooming in response to optogenetic activation are calcium ions. Conversely, induction of grooming and anxiety in mice produces calcium transients within microglia. Unexpectedly, calcium transients are not produced in Hoxb8 mutant mice in response to the induction of these behaviors. The likely cause for this lack of response by Hoxb8 mutant mice to induced grooming is the presence of high constitutive levels of free calcium within Hoxb8 mutant microglia resulting from the gene disruption. These calcium ions, in turn, serve as relentless signals to increase anxiety and grooming leading to chronic anxiety and pathological overgrooming in Hoxb8 mutant mice. Thus, we have shown that calcium signaling is used by microglia: 1) to induce anxiety and/or grooming by optogenetic stimulation of Hoxb8 microglia in WT mice, 2) to respond by microglia to the induction of both behaviors in WT mice and 3) as the causative agent for producing chronic anxiety and pathological overgrooming in Hoxb8 mutant mice.
Pleiotropic modulation of the gut-brain-lung axis by ketamine and its enantiomers.
Zhao X, Zhang X, Yuan S … +2 more , Hashimoto K, Zhang J
Mol Psychiatry · 2026 Apr · PMID 41974884 · Publisher ↗
Ketamine, a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely used for anesthesia and analgesia and, because of its rapid antidepressant effects, in psychiatry. Increasing evidence suggests that ketamine...
Ketamine, a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely used for anesthesia and analgesia and, because of its rapid antidepressant effects, in psychiatry. Increasing evidence suggests that ketamine and its enantiomers-(R)-ketamine (arketamine) and (S)-ketamine (esketamine)-also modulate systemic immunity and provide organ protection, partly through interactions with the gut microbiota, microbial metabolites, and intestinal immune-cell trafficking. However, these gut-mediated pathways must be distinguished from ketamine's well-established direct central and peripheral actions. In this review, we summarize how ketamine engages the gut-brain and gut-lung axes, emphasizing anti-inflammatory, immunoregulatory, and barrier-protective effects, while critically evaluating the evidence for causality in gut-organ communication. Along the gut-brain axis, ketamine is associated with restoration of microbial balance, normalization of short-chain fatty acid levels, and reduced migration of gut-derived γδ T17 and Th17 cells to the central nervous system, correlating with attenuated neuroinflammation and depressive-like behaviors. Through the gut-lung axis, ketamine has been reported to limit bacterial translocation and mesenteric lymph-associated inflammatory signaling and reduces pulmonary infiltration of pro-inflammatory cells, suggesting potential relevance in acute lung injury and other respiratory disorders. We also discuss enantiomer-specific effects: arketamine appears to provide more sustained neuroprotection and may be associated with fewer adverse effects than esketamine. Overall, these findings suggest the broad therapeutic potential of ketamine and its enantiomers for neuropsychiatric and inflammatory diseases, while underscoring the need for careful evaluation of long-term safety, optimal dosing, microbiota-targeted adjunctive strategies, and causal studies to distinguish direct pharmacological actions from indirect, microbiota-mediated effects.
Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.
Wang J, Chen L, Wang Z … +16 more , Chen XY, Zhang S, Ding D, Zhou Y, Rager-Aguiar R, Lin G, Zhang H, Boda VK, Ortyl TC, Nelson PT, Bezprozvanny I, Zhou FM, Du J, Wu Z, Li W, Liao FF
Mol Psychiatry · 2026 Apr · PMID 41965896 · Publisher ↗
Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3...
Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.
Multi-omics and electrophysiological examination of GABA receptors in the dorsolateral prefrontal cortex of humans with alcohol use disorder.
Granchi J, Salameh B, Miller B … +8 more , Scaduto P, Russell WK, Meyer TD, Teixeira AL, Fries GR, Stertz L, Walss-Bass C, Limon A
Mol Psychiatry · 2026 Apr · PMID 41965895 · Publisher ↗
Alterations of GABA receptors (GABARs) following chronic alcohol are thought to be related to deficits in GABAergic signaling in individuals with alcohol use disorder (AUD). Whether those modifications affect the functio...
Alterations of GABA receptors (GABARs) following chronic alcohol are thought to be related to deficits in GABAergic signaling in individuals with alcohol use disorder (AUD). Whether those modifications affect the function of synaptic GABARs is not clear, as the electrophysiological characterization of native synaptic receptors from AUD individuals had not been done. To obtain this information, we microtransplanted synaptic membranes from postmortem dorsolateral prefrontal cortex (DLPFC) samples of AUD and non-AUD subjects to determine functional traits of GABARs. To follow the path from transcription to function of potential changes of GABARs in AUD, GABARs currents and GABA pEC values were integrated with RNA-Seq and label-free proteomics datasets of bulk tissue and isolated synaptosomes from the same subjects. Our results outline significant reconfigurations in transcriptomic organization of GABARs in AUD, higher levels of GABRG1 and significant decrease of mitochondrial transcripts in AUD individuals. Notably, transcriptional differences were gradually lost as the analysis moved from transcription to protein and function within our cohort. This suggests post-translational buffering in AUD resulting in unchanged GABA receptor synaptic activity. Our novel findings establish a proof of concept for reactivating AUD post-synaptic receptors and integrating this information with multiple levels of multi-omic analyses, as well as outline hypothesis-generating insights into this multifaceted disease.
Adolescent disordered eating and epigenetic age acceleration.
Curtis M, Balfour D, Melton P … +3 more , Lin A, Kleinig Z, Cohen-Woods S
Mol Psychiatry · 2026 Apr · PMID 41963675 · Publisher ↗
Disordered eating is associated with a range of poor health outcomes that affect various body systems, including immune, metabolic, and stress-related processes. Biological ageing represents a potential mechanism through...
Disordered eating is associated with a range of poor health outcomes that affect various body systems, including immune, metabolic, and stress-related processes. Biological ageing represents a potential mechanism through which disordered eating may impact these processes and can be measured through epigenetic age acceleration. Epigenetic age acceleration has been explored in various psychiatric disorders, but no study has investigated epigenetic age acceleration in those with eating disorders, or disordered eating. The present study examined the association between disordered eating at ages 14 and 17, and epigenetic age acceleration at age 17 in a representative community cohort (N = 797). Disordered eating was assessed using global scores on the Eating Disorder Examination Questionnaire (EDE-Q), as well as scores on behavioural items relating to restriction, bingeing, and purging. After FDR correction, restriction at age 14 was longitudinally associated with a small (β = 0.09) increase in DunedinPACE, but not PhenoAge, GrimAge, Horvath, or Hannum. The association between age 14 restriction and DunedinPACE was partially mediated through higher BMI at ages 14 and 17, consistent with a role for BMI in the adverse health outcomes associated with disordered eating. No concurrent relationships were found between disordered eating at age 17 and epigenetic age acceleration. Findings suggest that third generation clocks may capture some of the long-term biological correlates of disordered eating, but - because the effect was small - it may not be clinically relevant. Replication using large community samples is required, along with studies that measure disordered eating and epigenetic age at multiple time points, to enhance causal inference.
Analysis of rare coding variants in schizophrenia-associated genes and generalised cognition in the UK Biobank.
Fenner E, Holmans P, O'Donovan MC … +3 more , Owen MJ, Walters JTR, Rees E
Mol Psychiatry · 2026 Apr · PMID 41963674 · Publisher ↗
Cognitive impairments in schizophrenia are associated with poor outcomes and are largely unimproved by current medications. It remains uncertain to what extent cognitive impairments arise from shared aetiology and biolog...
Cognitive impairments in schizophrenia are associated with poor outcomes and are largely unimproved by current medications. It remains uncertain to what extent cognitive impairments arise from shared aetiology and biology with schizophrenia, or are a consequence of having the condition. We analysed exome-sequencing data from 76,783 UK Biobank participants without schizophrenia to test for association between generalised cognition (g) and rare (minor allele count ≤ 5) variants in schizophrenia-associated genes. Protein-truncating and deleterious missense variants in loss-of-function intolerant genes were associated with lower g. Significantly stronger effects on g were found for protein-truncating variants in genes implicated in schizophrenia by rare coding variation, and for deleterious missense variants in credible causal genes at schizophrenia common allele loci. These findings indicate that biological processes disrupted in schizophrenia by common and rare variants are associated with g in unaffected individuals, suggesting the relationship between impaired cognition and schizophrenia reflects, in part, a shared underlying biology.
The Cognitive benefits of nitrate in patients with alcohol use disorder: unraveling the oral microbiome ectopic colonization pathway.
Li X, Zhao K, Chen J … +14 more , Ni Z, Li L, Chen Y, Shi W, Zhang Y, Gao X, Wang C, Gu L, Dong Y, Shi J, Liu Y, Su L, Xue YX, Sun H
Mol Psychiatry · 2026 Apr · PMID 41957179 · Publisher ↗
Our prior research revealed that dietary nitrate (NO₃⁻) may mitigate alcohol-induced cognitive impairment through oral microbiota modulation and attenuation of inflammatory responses in mice. While alcohol use disorder (...
Our prior research revealed that dietary nitrate (NO₃⁻) may mitigate alcohol-induced cognitive impairment through oral microbiota modulation and attenuation of inflammatory responses in mice. While alcohol use disorder (AUD) is known to associate with cognitive decline and gut dysbiosis, the therapeutic potential of nitrate supplementation in ameliorating these effects remains to be elucidated. In this randomized, double-blind, placebo-controlled pilot trial (NCT05963659), 70 AUD patients received either nitrate-rich beetroot juice or placebo for 14 days. Primary outcomes were spatial memory measured by Cambridge Neuropsychological Test Battery. Oral and gut microbiota were analyzed before and after intervention by 16S rRNA sequencing. To establish causality, germ-free (GF) mice were colonized with pre- and post-nitrate intervention saliva samples from AUD patients, followed by microbiota profiling across gastrointestinal regions. The mean difference in Delayed Matching to Sample (all delays) change between the nitrate consumption group and the placebo group after intervention was 9.784 (95%[CI], 1.85-17.72, P = 0.016), as analyzed using a generalized linear mixed model. Nitrate supplementation induced distinct shifts in oral microbiota, while gut microbiota exhibited less pronounced changes. GF mice receiving pre-intervention microbiota exhibited elevated Klebsiella abundance throughout the gut. Mechanistically, nitrate attenuated systemic inflammation, enhanced intestinal barrier integrity, and improved cognitive performance in mice. Dietary nitrate enhances cognitive function in AUD patients, partially mediated by ectopic colonization of oral microbiota. Our findings identify specific oral bacteria (e.g., Klebsiella) as key contributors to alcohol-induced cognitive impairment and suggest promising therapeutic potential for microbiota-targeted interventions in AUD.
Subjective and neurocognitive profiling of clinical doses of 3,4-methylenedioxymethamphetamine (MDMA) in healthy volunteers: implications for therapeutic use.
Ramaekers JG, Kuypers KPC, Vollenweider FX
Mol Psychiatry · 2026 Apr · PMID 41951837 · Publisher ↗
MDMA's history spans military experimentation, recreational use, and clinical trials for PTSD treatment, reflecting both promise and controversy. While studies in heavy users suggested possible neurotoxicity, evidence re...
MDMA's history spans military experimentation, recreational use, and clinical trials for PTSD treatment, reflecting both promise and controversy. While studies in heavy users suggested possible neurotoxicity, evidence remains inconclusive. Clinical trials show that one to three sessions of MDMA-assisted psychotherapy can alleviate PTSD symptoms, yet regulators have criticized inadequate reporting of (positive) adverse events. To clarify safety, this narrative review examines placebo-controlled single-dose studies in healthy volunteers, focusing on MDMA's acute and subacute effects on subjective state and neurocognitive function relevant to therapeutic applications. Single doses of 75-125 mg enhance mood, empathy, trust, arousal, and prosocial feelings through monoamine reuptake inhibition and release. Post-acutely, transient monoamine depletion may cause fatigue and low mood. During intoxication, MDMA transiently impairs memory encoding via increased 5-HT signaling and 5-HT2A activation but does not heighten suggestibility. Inhibitory control and executive function are largely preserved, while motor coordination and cognitive flexibility decline modestly. These effects vary with metabolism, immune response, drug interactions, and context, underscoring the need for personalized monitoring. It is inferred that, acutely, positive affect may enhance therapeutic alliance and openness as well as susceptibility to boundary violations; amnestic effects may support trauma processing by facilitating fear extinction and disrupting negative memory reconsolidation; whereas temporary reductions in attention and cognitive flexibility may call for structured, emotionally focused therapeutic settings. MDMA's distinct neurocognitive profile offers clinical promise but complicates trial design by compromising blinding and inflating expectancy, necessitating their quantitative assessments and inclusion of similar comparator drugs to ensure reliable evaluation of efficacy.
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