Biology subjects

Maric, D.

Publications and source records attributed to Maric, D..

18 recordsLinked to original sources

bioRxiv2026

Targeting GPR183 to reduce peripheral sensitization: evidence from rodent and human tissue analyses

Peripheral sensitization is a key process in the development of painful inflammatory conditions, driven in part by immune-cell mediator release following tissue injury. The G protein-coupled receptor, GPR183, predominantly expressed on immune cells, regulates their migration, positioning, and mediator production. Yet its role in peripheral sensitization and the specific immune cells involved remains insufficiently understood. In rats, intraplantar injection of 7,25-dihydroxycholesterol (7,25-OHC), the most potent endogenous GPR183 ligand, produced long-lasting nociception that was prevented by the selective GPR183 antagonist SAE-14. Because GPR183 activates ERK signaling, which influences pain pathways including nitric oxide synthase (NOS) activity and NO formation, we used NOS inhibitors and knockout animals to test the contribution of inducible and neuronal NOS isoforms to 7,25-OHC-induced sensitization. We found that both isoforms influence this response, independent of cyclooxygenases. In a well-characterized rat incisional injury model, GPR183 protein expression increased in injured paw tissue, and SAE-14 reversed hypersensitivity. Meta-analysis of human post-surgical skin samples similarly showed elevated GPR183 expression and transcriptional changes favoring 7,25-OHC production after injury. We identified macrophages and Langerhans cells (LCs) as the principal GPR183-expressing cell types in human skin. LC ablation studies revealed that 7,25-OHC-evoked hypersensitivity does not depend on LCs, implicating GPR183+ macrophages as predominant drivers of GPR3-induced hypersensitivity. Overall, our findings define the cellular and molecular pathways linking GPR183 to peripheral sensitization and highlight GPR183 antagonism as a promising strategy for pain management.

pharmacology and toxicology↗

bioRxiv2025

Variable Schwann cell merlin inactivation is targetable with TEAD1 inhibition in schwannomas.

Schwann cell tumors occur frequently in association with the vestibular nerves, leading to sensorineural hearing loss, and brainstem compression. In humans, unilateral vestibular schwannomas (VS) occur sporadically (VSspo)1, or bilaterally with neurofibromatosis type 2 syndrome (NF2) - VSnf2.2 VS formation is driven by sub-haploid NF2 gene dosage3, typically by biallelic loss.4,5 Loss of merlin promotes hippo/TEAD dependent transcriptional reprogramming, proliferation, and paracrine signaling that varies across time, and tumor volume.4,6 These variations lead to a clinically unpredictable course, and incomplete response to treatment. We hypothesized that Schwann cell merlin inactivation state determines cell-wise hippo/TEAD dependency and drives schwannoma pathogenesis. We analyzed clinical samples from VSspo and VSnf2 with a multi-omics approach and detected variation in merlin activity within tumor Schwann cell population. We found that tumor-driving merlin-depleted Schwann cells (Schwannmer-) exhibited elevated hippo activity that was predominantly driven by TEAD1. In-silico TEAD1 perturbation led to a reversal to merlin intact Schwann phenotype. These findings, and tumor cell growth suppression were confirmed in NF2fl/fl;Peri-Cre mouse model7, and in human derived schwannoma cells treated with a pan-TEAD auto palmitoylation inhibitor VT3989.8 Our computational and experimental results confirm that TEAD1 inhibition could be a potent, targeted strategy for schwannomas.

cancer biology↗

bioRxiv2025

Phosphoproteomic dysregulation drives tumor proliferation in Cushing's disease

Pituitary adenomas constitute up to 20% of primary brain tumors, yet somatic mutations are only found in 15% of pituitary adenomas. Epigenomic dysregulation has been proposed as a tumorigenic mechanism in pituitary adenomas causing Cushings disease (CD). We created paired datasets of human CD adenomas and en-route margin adult human pituitary glands and assayed their chromatin accessibility, DNA methylation, transcriptomic, proteomic and phospho-proteomic landscapes. In CD adenomas, we found epigenetic reactivation of a neurodevelopmental phosphoprotein program typically lost in the post-natal pituitary gland. CD cells overexpressed PPP1R17, a potent endogenous inhibitor of the ubiquitous protein phosphatase PP2A. Mechanistically, PPP1R17 overexpression in normal murine pituitary cells recapitulated the adenoma phenotype, and PPP1R17-mediated tumorigenesis was reversible using an FDA-approved small molecule PP2A agonist both in-vitro and in-vivo. Our findings highlight aberrant peptide phosphorylation as a targetable mechanism in CD. Significance statementCushings disease (CD) causes significant morbidity and mortality despite best medical and surgical treatment. Surgery is the mainstay of treatment, but carries perioperative risks and is frequently followed by remission. There is a paucity of effective medical treatments, due in part to a limited understanding of tumor mechanisms. The majority of CD adenomas are wild-type, with no known causal mutations. Our study identifies phosphoproteomic dysregulation as a mechanism of CD tumorigenesis common to wild-type and mutant CD adenomas. We target this pathway in-vivo and in-vitro using an FDA-approved small molecule. Our study proposes a novel therapeutic strategy for patients with CD.

cancer biology↗

bioRxiv2024

Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8+ T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

cancer biology↗

bioRxiv2024

Maintenance of neuronal TDP-43 expression requires axonal lysosome transport

TDP-43 mislocalization and pathology occurs across a range of neurodegenerative diseases, but the pathways that modulate TDP-43 in neurons are not well understood. We generated a Halo-TDP-43 knock-in iPSC line and performed a genome-wide CRISPR interference FACS-based screen to identify modifiers of TDP-43 levels in neurons. A meta-analysis of our screen and publicly available screens identified both specific hits and pathways present across multiple screens, the latter likely responsible for generic protein level maintenance. We identified BORC, a complex required for anterograde lysosome transport, as a specific modifier of TDP-43 protein, but not mRNA, levels in neurons. BORC loss led to longer half-life of TDP-43 and other proteins, suggesting lysosome location is required for proper protein turnover. As such, lysosome location and function are crucial for maintaining TDP-43 protein levels in neurons.

neuroscience↗

bioRxiv2024

Age Dependent Integration of Cortical Progenitors Transplanted at the Adult CSF-Brain Interface

There has been renewed interest in neural transplantation of cells and tissues for brain repair. Recent studies have demonstrated the ability of transplanted neural precursor cells and in vitro grown organoids to mature and locally integrate into host brain neural circuitry. Much effort has focused on how the transplant behaves and functions after the procedure, but the extent to which the host brain can properly innervate the transplant, particularly in the context of aging, is largely unexplored. Here we report that transplantation of rat embryonic cortical precursor cells into the cerebrospinal fluid-subventricular zone (CSF-SVZ) of adult rat brains generates a brain-like tissue (BLT) at an ectopic site. This model allows for the assessment of long-range connectivity and cellular interactions between the transplant and the host brain as a function of host age. The transplanted precursor cells initially proliferate, then differentiate, and develop into mature BLTs, which receive supportive cellular components from the host including blood vessels, microglia, astrocytes, and oligodendrocytes. There was integration of the BLT into the host brain which occurred at all ages studied, suggesting that host age does not affect the maturation and integration of the transplant-derived BLT. Long-range axonal projections from the BLT into the host brain were robust throughout the different aged recipients. However, long-distance innervation originating from the host brain into the BLT significantly declined with age. This work demonstrates the feasibility and utility of integrating new neural tissue structures at ectopic sites into adult brain circuits to study host-transplant interactions.

neuroscience↗

bioRxiv2024

Endogenously produced hydrogen cyanide serves as a novel mammalian gasotransmitter

Small, gaseous molecules, known as gasotransmitters (NO, CO, H2S), are produced endogenously in mammalian cells and serve important biological roles. Hydrogen cyanide, traditionally considered a cytotoxic molecule in mammals, serves as an endogenous mediator in several plants and bacterial species. Here we show that low concentrations of cyanide are generated endogenously in mouse liver and human hepatocytes. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. Cyanide, in turn, is detectable in several cellular compartments. Cyanide is also detectable basally in the blood of mice; its levels increase after treatment of the animals with glycine. Rhodanese activity regulates endogenous cyanide levels. Cyanide, when generated endogenously at an optimal level, exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation. Dysregulation of endogenous cyanide, either below or above optimal levels, impairs cellular bioenergetics. The regulatory effects of cyanide are in part mediated by posttranslational modification of cysteine residues via protein cyanylation; cyanylated protein residues can be detected basally, and increase after treatment with glycine. Controlled low-dose cyanide supplementation exhibits cytoprotective effects, as demonstrated in hypoxia and reoxygenation models in vitro and in vivo. However, pathologically elevated cyanide production, as demonstrated in nonketotic hyperglycinemia - an autosomal recessive disease of glycine metabolism - is deleterious to the cells.

biochemistry↗

bioRxiv2024

Metabolic Quadrivalency in RSeT Human Embryonic Stem Cells

One of the most important properties of human embryonic stem cells (hESCs) is related to their pluripotent states. In our recent study, we identified a previously unrecognized pluripotent state induced by RSeT medium. This state makes primed hESCs resistant to conversion to naive pluripotent state. In this study, we have further characterized the metabolic features in these RSeT hESCs, including metabolic gene expression, metabolomic analysis, and various functional assays. The commonly reported metabolic modes include glycolysis or both glycolysis and oxidative phosphorylation (i.e., metabolic bivalency) in pluripotent stem cells. However, besides the presence of metabolic bivalency, RSeT hESCs exhibited a unique metabolome with additional fatty acid oxidation and imbalanced nucleotide metabolism. This metabolic quadrivalency is linked to hESC growth independent of oxygen tension and restricted capacity for naive reprogramming in these cells. Thus, this study provides new insights into pluripotent state transitions and metabolic stress-associated hPSC growth in vitro.

biochemistry↗

bioRxiv2024

Resistance to Naive and Formative Pluripotency Conversion in RSeT Human Embryonic Stem Cells

One of the most important properties of human embryonic stem cells (hESCs) is related to their primed and naive pluripotent states. Our previous meta-analysis indicates the existence of heterogeneous pluripotent states derived from diverse naive protocols. In this study, we have characterized a commercial medium (RSeT)-based pluripotent state under various growth conditions. Notably, RSeT hESCs can circumvent hypoxic growth conditions as required by naive hESCs, in which some RSeT cells (e.g., H1 cells) exhibit much lower single cell plating efficiency, having altered or much retarded cell growth under both normoxia and hypoxia. Evidently, hPSCs lack many transcriptomic hallmarks of naive and formative pluripotency (a phase between naive and primed states). Integrative transcriptome analysis suggests our primed and RSeT hESCs are close to the early stage of post-implantation embryos, similar to the previously reported primary hESCs and early hESC cultures. Moreover, RSeT hESCs did not express naive surface markers such as CD75, SUSD2, and CD130 at a significant level. Biochemically, RSeT hESCs exhibit a differential dependency of FGF2 and co-independency of both Janus kinase (JAK) and TGF{beta} signaling in a cell-line-specific manner. Thus, RSeT hESCs represent a previously unrecognized pluripotent state downstream of formative pluripotency. Our data suggest that human naive pluripotent potentials may be restricted in RSeT medium. Hence, this study provides new insights into pluripotent state transitions in vitro.

cell biology↗

bioRxiv2023

Single-cell multiomic analysis reveals the involvement of Type I interferon-responsive CD8+ T cells in amyloid beta-associated memory loss

Alzheimers disease (AD) is the leading cause of dementia worldwide, but there are limited therapeutic options and no current cure. While the involvement of microglia in AD has been highly appreciated, the role of other innate and adaptive immune cells remains largely unknown, partly due to their scarcity and heterogeneity. This study aimed to study non-microglial immune cells in wild type and AD-transgenic mouse brains across different ages. Our results uncovered the presence of a unique CD8+ T cell population that were selectively increased in aging AD mouse brains, here referred to as "disease-associated T cells (DATs)". These DATs were found to express an elevated tissue-resident memory and Type I interferon-responsive gene signature. Further analysis of aged AD mouse brains showed that these CD8+ T cells were not present in peripheral or meningeal tissues. Preventing CD8+ T cell development in AD-transgenic mice via genetic deletion of beta-2 microglobulin (B2m) led to a reduction of amyloid-{beta} plaque formation in aged mice, and improved memory in AD-transgenic mice as early as four months of age. The integration of transcriptomic and epigenomic profiles at the single-cell level revealed potential transcription factors that reshape the regulomes of CD8+ T cells. These findings highlight a critical role for DATs in the progression of AD and provide a new avenue for treatment.

immunology↗

bioRxiv2023

Temporal and spatial characterization of HIV/SIV infection at anorectal mucosa using rhesus macaque rectal challenge model

The study described herein is a continuation of our work in which we developed a methodology to identify small foci of transduced cells following rectal challenge of rhesus macaques with a non-replicative luciferase reporter virus. In the current study, the wild-type virus was added to the inoculation mix and twelve rhesus macaques were necropsied 2-4 days after the rectal challenge to study the changes in infected cell phenotype as the infection progressed. Relying on luciferase reporter we noted that both anus and rectum tissues are susceptible to the virus as early as 48h after the challenge. Small regions of the tissue containing luciferase-positive foci were further analyzed microscopically and were found to also contain cells infected by wild-type virus. Phenotypic analysis of the Env and Gag positive cells in these tissues revealed the virus can infect diverse cell populations, including but not limited to Th17 T cells, non Th17 T cells, immature dendritic cells, and myeloid-like cells. The proportions of the infected cell types, however, did not vary much during the first four days of infection when anus and rectum tissues were examined together. Nonetheless, when the same data was analyzed on a tissue-specific basis, we found significant changes in infected cell phenotypes over the course of infection. For anal tissue, a statistically significant increase in infection was observed for Th17 T cells and myeloid-like cells, while in the rectum, the non-Th17 T cells showed the biggest temporal increase, also of statistical significance. IMPORTANCEMen who have sex with men are at the highest risk of acquiring HIV via receptive anal intercourse. Understanding what sites are permissive to the virus, and what the early cellular targets are is critical for development of effective prevention strategies to control HIV acquisition amid receptive anal intercourse. Our work sheds light on the early HIV/SIV transmission events at the rectal mucosa by identifying the infected cells and highlights the distinct roles that different tissues play in virus acquisition and control.

immunology↗

bioRxiv2021

Early detection of cerebrovascular pathology and protective antiviral immunity by MRI

Central nervous system (CNS) infections are a major cause of human morbidity and mortality worldwide. Even patients that survive CNS infections can have lasting neurological dysfunction resulting from immune and pathogen induced pathology. Developing approaches to noninvasively track pathology and immunity in the infected CNS is crucial for patient management and development of new therapeutics. Here, we develop novel MRI-based approaches to monitor virus-specific CD8+ T cells and their relationship to cerebrovascular pathology in the living brain. We studied a relevant murine model in which a neurotropic virus (vesicular stomatitis virus) was introduced intranasally and then entered the brain via olfactory sensory neurons - a route exploited by many pathogens in humans. Using T2*-weighted high-resolution MRI, we identified small cerebral microbleeds as the earliest form of pathology associated with viral entry into the brain. Mechanistically, these microbleeds occurred in the absence of peripheral immune cells and were associated with infection of vascular endothelial cells. We monitored the adaptive response to this infection by developing methods to iron label and track individual virus specific CD8+ T cells by MRI. Transferred antiviral T cells were detected in the brain within a day of infection and were able to reduce cerebral microbleeds. These data demonstrate the utility of MRI in detecting the earliest pathological events in the virally infected CNS as well as the therapeutic potential of antiviral T cells in mitigating this pathology.

neuroscience↗

bioRxiv2021

Androglobin, a chimeric mammalian globin, is required for male fertility

Spermatogenesis is a highly specialised process, involving multiple dedicated pathways and regulatory check-points. Defects ultimately lead to male sub-fertility or sterility, and numerous aspects of mammalian sperm formation remain unknown. The predominant expression of the latest globin family member, androglobin (Adgb) in mammalian testis tissue prompted us to assess its physiological function in spermatogenesis. Adgb knockout mice display male infertility, reduced testis weight, impaired maturation of elongating spermatids, abnormal sperm shape and ultrastructural defects in microtubule and mitochondrial organisation. Epididymal sperm from Adgb knockout animals display multiple flagellar malformations including coiled, bifide or shortened flagella, and erratic acrosomal development. Following immunoprecipitation and mass spectrometry, we could identify septin 10 (Sept10) as interactor of Adgb. The Sept10-Adgb interaction was confirmed both in vivo using testis lysates, and in vitro by reciprocal co-immunoprecipitation experiments. Furthermore, absence of Adgb leads to mislocalisation of Sept10 in sperm, indicating defective manchette and sperm annulus formation. Finally, in vitro data suggest that Adgb contributes to Sept10 proteolysis in a calmodulin (CaM)-dependent manner. Collectively, our results provide evidence that Adgb is essential for murine spermatogenesis and further suggest that interdependence between Adgb and Sept10 is required for sperm head shaping via the manchette and proper flagellum formation.

developmental biology↗

bioRxiv2021

Transcriptional heterogeneity of ventricular zone cells throughout the embryonic mouse forebrain

The ventricular zone (VZ) of the nervous system contains radial glia cells that were originally considered relatively homogenous in their gene expression. However, a detailed characterization of transcriptional diversity in these VZ cells has not been reported. Here, we performed single-cell RNA sequencing to characterize transcriptional heterogeneity of neural progenitors within the VZ and subventricular zone (SVZ) of the mouse embryonic cortex and ganglionic eminences (GEs). By using a transgenic mouse line to enrich for VZ cells, we detect significant transcriptional heterogeneity within VZ and SVZ progenitors, both between forebrain regions and within spatial subdomains of specific GEs. Additionally, we observe differential gene expression between E12.5 and E14.5 VZ cells, which could provide insights into temporal changes in cell fate. Together, our results reveal a previously unknown spatial and temporal genetic diversity of telencephalic VZ cells that will aid our understanding of initial fate decisions in the forebrain.

neuroscience↗

bioRxiv2021

Simultaneous in vivo Pharmacokinetics and Pharmacodynamics of TDF Intravaginal Ring during High-dose Vaginal SHIV Challenge in Pigtail Macaques

The demonstration of complete protection of macaques in a repeated low dose virus challenge by a tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR) and the success of the dapivirine IVR in clinical trials highlighted the potential of IVRs as pre- exposure prophylaxis against HIV. Efficacy of TDF ring was not investigated in sexually active women. Our understanding of the mechanisms of protection is limited. To address this knowledge gap, we performed simultaneous pharmacokinetic and pharmacodynamic analysis of a TDF-IVR at the site of SIV challenge in pigtail macaques at the anatomical and cellular level. Specifically, we challenged TDF-IVR administered pigtail macaques with a single high dose of a non-replicative SIV-based vector containing a dual reporter system that helped us to identify the earliest targets of SIV infection within the mucosa. Two and three days after challenge, the macaques were euthanized and tenofovir (TFV) concentrations were measured in the female reproductive tract (FRT) by HPLC-MS/MS to correlate drug concentrations and SIV-vector transduction efficiency. TFV formed a gradient through the mucosal tissue, with the highest concentrations near the ring, in the upper vagina and endocervix. Despite this, several transduction events were identified with the most common sites being in the ovaries. Moreover, proviral DNA was detected in the cervix and vagina. Thus, our studies demonstrate an uneven distribution of TFV in the FRT of macaques after release from a TDF-IVR that leads to incomplete FRT protection from high viral dose challenge.

pharmacology and toxicology↗

bioRxiv2021

A Single Cell Atlas of Spared Tissue Below a Spinal Cord Injury Reveals Cellular Mechanisms of Repair

After spinal cord injury (SCI), the "spared" tissue below the lesion contains undamaged cells that could support or augment recovery, but targeting these cells requires a clearer understanding of their injury responses and capacity for repair. Here, we used single nucleus sequencing to profile how each cell type in the lumbar spinal cord changes over time after a thoracic injury. We present an atlas of these dynamic responses and explore two unexpected findings. Amongst neurons, rare cell types expressed a molecular signature of regeneration and amongst microglia, we identified a population of "trauma associated microglia" (TAM). These TAM cells were present in the white matter near degenerating axons and expressed the trophic factors Igf1 and Spp1(OPN). Viral over-expression of Igf1 and Spp1(OPN) expanded the TAM population and promoted the clearance of myelin debris. These findings expose endogenous mechanisms of repair in spared neural tissue, uncovering potential candidates for targeted therapy.

neuroscience↗

bioRxiv2021

Th17 T cells and immature dendritic cells are the preferential initial targets after rectal challenge with an SIV-based replication-defective dual-reporter vector

Understanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containing foci of luminescent, transduced cells were identified macroscopically using an in vivo imaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6+ T cells--the vast majority of which express ROR{gamma}T, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission. IMPORTANCEMen and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. While in vitro data have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.

immunology↗

bioRxiv2020

NMDAR-mediated transcriptional control of geneexpression in the specification of interneuron subtype identity

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+ and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical and physiological properties. However, the molecular mechanisms regulating their diversity remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific conditional Grin1 loss results in a systemic downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders, particularly schizophrenia. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

neuroscience↗