Cell-specific Functions Research Articles

REVIEW OF LITERATURE ON NANOSCALE TOPOGRAPHIC MODIFICATION, MAGNETIC NANOPARTICLES, AND THEIR ROLES IN OSSEOINTEGRATION AND BONE TISSUE ENGINEERING

Here, we will review together the roles of nanoscale modification of titanium substrates and use of magnetic nanoparticles in osseointegration and bone tissue engineering. The technological advances in nanotechnology that has been achieved create new measures to increase the implants-biological systems for an optimal osseointegration through improving important cell-specific functions. We systematically review nanoscale surface modification techniques of titanium implants, covering their physicochemical properties, influence on cellular behaviors and clinical relevances. The report also lengthy discusses the clinical applicability of magnetic nanoparticles for drug and gene delivery systems, targeted cancer therapy as well bone tissue engineering regulting their intrinsic superparamagnetism properites, biocompatibility with other therapies etc. We present detailed review of these technologies and their potential applications in clinical settings.

Advances in understanding the role of immune checkpoint LAG-3 in tumor immunity: a comprehensive review.

Lymphocyte activation gene 3 (LAG-3), also known as CD223, is an emerging immune checkpoint that follows PD-1 and CTLA-4. Several LAG-3 targeting inhibitors in clinical trials and the combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) have been approved for treating - unresectable or metastatic melanoma. Despite the encouraging clinical potential of LAG-3, the physiological function and mechanism of action in tumors are still not well understood. In this review, we systematically summarized the structure of LAG-3, ligands of LAG-3, cell-specific functions and signaling of LAG-3, and the current status of LAG-3 inhibitors under development.

Development of Non-Invasive miRNA Markers for Assessing the Quality of Human Induced Pluripotent Stem Cell-Derived Retinal Organoids.

Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for their application in research. However, traditional methods such as morphological evaluation and immunohistochemical analysis have limitations due to their lack of precision and invasiveness, respectively. This study aims to identify non-invasive biomarkers for RO differentiation quality using exosomal microRNAs (miRNAs), which are known to reflect cell-specific functions and development in the retina. We differentiated ROs from human induced pluripotent stem cells (hiPSCs) and classified them into 'superior' and 'inferior' groups based on morphological and immunohistochemical criteria. Exosomes from the conditioned media were isolated and analyzed for miRNA content. Our findings revealed distinct miRNA profiles between superior and inferior ROs, with superior ROs exhibiting higher miRNA diversity and specifically up- or down-regulated miRNAs. Gene ontology and pathway enrichment analyses indicated that the target genes of these miRNAs are involved in neuron proliferation and differentiation. The study suggests the potential of exosomal hsa-miR-654-3p and hsa-miR-451a as non-invasive biomarkers for real-time monitoring of RO quality, facilitating the development of standardized, efficient, and cost-effective culture methods.

Melatonin via MTNR1B regulates METTL3 to protect ileum cell differentiation.

Intestinal stem cells rapidly differentiate into various epithelial cells, playing a crucial role in maintaining intestinal homeostasis. Melatonin, a known endogenous molecule with anti-inflammatory and antioxidant properties, has its potential efficacy in ileum stem cells differentiation not fully understood to date. This study indicates that melatonin suppresses ileum inflammation and maintains normal differentiation of ileum stem cells through MTNR1B. Subsequent outcomes following treatment with MTNR1B inhibitors further substantiate these findings. Additionally, overexpression of METTL3 protein appears to be a potential instigator for promoting ileum inflammation and disruptions in cell differentiation. Treatment with the METTL3 inhibitor SAH significantly inhibits ileum inflammation and Wnt/β-catenin activity, thereby sustaining normal cellular differentiation functions. In summary, this study showed that melatonin may improve ileum inflammation and maintain cell differentiation functions by inhibiting abnormal METTL3 expression via MTNR1B.

Mitochondria-targeted and photo-activated CO release for synergistic photodynamic therapy

In photodynamic therapy, organelle-targeted strategies are allowed to selectively impair specific cell functions, leading to efficiently eliminating cancer cells. Carbon monoxide (CO), as a highly toxic gaseous signaling molecule, often plays an active role in enhancing the sensitivity of cancer cells during cancer treatment, making cells prone to apoptosis. Therefore, we report a photosensitizer Cy-Mn, which possesses the capability of photoactivatable CO releasing and 1O2 generation. Furthermore, during the treatment, Cy-Mn has perfect synergistic effect on the cancer cells for enhanced photodynamic therapy. Under 760 nm laser irradiation, Cy-Mn released manganese ions, which altered the permeability transition pore of the mitochondria membrane, reduced the mitochondrial membrane potential, and exhibited severe phototoxicity. Additionally, we investigated the imaging of Cy-Mn in vivo, and found Cy-Mn displayed excellent fluorescence imaging capabilities, which further promotes its biological applications in imaging-guided PDT.

The application of organoids in colorectal diseases.

Intestinal organoids are a three-dimensional cell culture model derived from colon or pluripotent stem cells. Intestinal organoids constructed in vitro strongly mimic the colon epithelium in cell composition, tissue architecture, and specific functions, replicating the colon epithelium in an in vitro culture environment. As an emerging biomedical technology, organoid technology has unique advantages over traditional two-dimensional culture in preserving parental gene expression and mutation, cell function, and biological characteristics. It has shown great potential in the research and treatment of colorectal diseases. Organoid technology has been widely applied in research on colorectal topics, including intestinal tumors, inflammatory bowel disease, infectious diarrhea, and intestinal injury regeneration. This review focuses on the application of organoid technology in colorectal diseases, including the basic principles and preparation methods of organoids, and explores the pathogenesis of and personalized treatment plans for various colorectal diseases to provide a valuable reference for organoid technology development and application.

Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101

T lymphocytes and myeloid cells express the Ig-like glycoprotein CD101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during DSS-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101-/- mice, animals with a Treg-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of Th1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101-/- x IFN- γ-/- mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of IBD patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory and anti-microbial pathways.

Lipid droplets in the nervous system: involvement in cell metabolic homeostasis.

Lipid droplets serve as primary storage organelles for neutral lipids in neurons, glial cells, and other cells in the nervous system. Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum. Previously, lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis; however, recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system. In addition to their role in regulating cell metabolism, lipid droplets play a protective role in various cellular stress responses. Furthermore, lipid droplets exhibit specific functions in neurons and glial cells. Dysregulation of lipid droplet formation leads to cellular dysfunction, metabolic abnormalities, and nervous system diseases. This review aims to provide an overview of the role of lipid droplets in the nervous system, covering topics such as biogenesis, cellular specificity, and functions. Additionally, it will explore the association between lipid droplets and neurodegenerative disorders. Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

Cannabinoid receptor type 1 activation causes a water diuresis by inducing an acute central diabetes insipidus in mice.

Cannabis and synthetic cannabinoid consumption are increasing worldwide. Cannabis contains numerous phytocannabinoids that act on the G protein-coupled cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 expressed throughout the body, including the kidney. Essentially every organ, including the kidney, produces endocannabinoids, which are endogenous ligands to these receptors. Cannabinoids acutely increase urine output in rodents and humans, thus potentially influencing total body water and electrolyte homeostasis. As the kidney collecting duct (CD) regulates total body water, acid/base, and electrolyte balance through specific functions of principal cells (PCs) and intercalated cells (ICs), we examined the cell-specific immunolocalization of CB1R in the mouse CD. Antibodies against either the C-terminus or N-terminus of CB1R consistently labeled aquaporin 2 (AQP2)-negative cells in the cortical and medullary CD and thus presumably ICs. Given the well-established role of ICs in urinary acidification, we used a clearance approach in mice that were acid loaded with 280 mM NH4Cl for 7 days and nonacid-loaded mice treated with the cannabinoid receptor agonist WIN55,212-2 (WIN) or a vehicle control. Although WIN had no effect on urinary acidification, these WIN-treated mice had less apical + subapical AQP2 expression in PCs compared with controls and developed acute diabetes insipidus associated with the excretion of large volumes of dilute urine. Mice maximally concentrated their urine when WIN and 1-desamino-8-d-arginine vasopressin [desmopressin (DDAVP)] were coadministered, consistent with central rather than nephrogenic diabetes insipidus. Although ICs express CB1R, the physiological role of CB1R in this cell type remains to be determined.NEW & NOTEWORTHY The CB1R agonist WIN55,212-2 induces central diabetes insipidus in mice. This research integrates existing knowledge regarding the diuretic effects of cannabinoids and the influence of CB1R on vasopressin secretion while adding new mechanistic insights about total body water homeostasis. Our findings provide a deeper understanding about the potential clinical impact of cannabinoids on human physiology and may help identify targets for novel therapeutics to treat water and electrolyte disorders such as hyponatremia and volume overload.

MicroRNA-127-3p regulates inflammatory response in injury-induced vascular remodeling and cellular senescence in vascular smooth muscle cells through mTor

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Martin-Luther-Universität Halle-Wittenberg Background and Purpose The accumulation of senescent cells in the vasculature contributes to impaired vascular function over the lifetime. Micro RNAs (miRs) are promising therapeutic targets due to their cell-specific functions. Targeting miR-127-3p emerges as an attractive approach to enhance vascular healing and limit angioplasty-related complications. Here, we focus on elucidating the role of miR-127-3p in vascular smooth muscle cells (VSMC) to characterize their role in cellular function and vascular senescence. Methods Utilizing reverse transcription and qRT-PCR we checked expression levels of miR-127-3p in human and murine aortic VSMCs. After overexpression and downregulation via transfection of pre-miR and antagomiR, we evaluated the influence of miR-127-3p on cellular functions such as proliferation and migration of human (non-) replicative senescent VSMCs. Potential targets were selected via target prediction analysis and verified on mRNA and protein levels. Morphological changes were visualized via high-resolution fluorescence microscopy. Senescence marker expression was checked after transfection by qRT-PCR. Results MiR-127-3p is highly upregulated in femoral artery tissue on day 10 after wire-induced injury in C57Bl6 mice, serving as restenosis model (p<0.001) and aged C57BL/6 mice (3 months vs. 22 months, p<0.0001). Replicative senescent human VSMC exhibit increased miR-127-3p expression (p<0.05). In vitro, miR-127-3p overexpression reduces proliferation in senescent (p<0.001) and non-senescent (p<0.01) cells. It hinders migration in non-senescent cells (p<0.0001) but has a reverse effect in senescent cells (p<0.01). Potential targets affecting cellular functions, inflammatory pathways, and cellular aging were identified as mTOR, AXL, and TEAD3 (p<0.05). Transfection of pre-miR leads to increase in cell size and the acquisition of a flattened morphology of human VSMC. P14arf and laminB1, as senescence-associated genes, showed downregulation after overexpression of miR-127-3p on mRNA level (p<0.05). When VSMCs were stimulated with anti-miR-127-3p, increased mRNA levels of p14arf and laminB1 were detected (p<0.05). Conclusion This study identifies miR-127-3p as a contributor to cellular functions including cellular proliferation and migration and seems to have opposing effects in non- and replicative senescent VSMC. Further research is needed to validate miR-127-3p as a therapeutic target for vascular aging and remodeling in vitro and in vivo.

Screening and Validation of Natural Products for Drug Discovery: Key Points and Approaches

This article highlights the key points and approaches involved in the screening and validation of natural products for drug discovery. Screening assays play a vital role in evaluating the biological activities of natural product extracts or fractions, targeting specific diseases, pathways, or cellular processes of interest. In vitro studies provide further insights into the efficacy, safety, and mechanism of action of promising candidates, using isolated cells or cellular components. Cell-based assays offer a more realistic cellular environment to assess natural product effects on cell viability, proliferation, and specific functions. Animal models bridge the gap between in vitro and clinical evaluations, providing a comprehensive understanding of therapeutic effects, pharmacokinetics, and toxicity profiles. Pharmacokinetic studies examine the absorption, distribution, metabolism, and excretion of natural products, optimizing dosage regimens and predicting human efficacy. Safety evaluation encompasses toxicity studies to determine safe dosage ranges and identify potential risks. Promising candidates progress to clinical trials, where efficacy, safety, dosage, and interactions are assessed in human subjects. This comprehensive screening and validation process contributes to the development of effective and safe natural product-based drugs.

Production and Functional Analysis of Collagen Hexapeptide Repeat Sequences in Pichia pastoris.

In the development of biomaterials with specific structural domains associated with various cellular activities, the limited integrin specificity of commonly used adhesion sequences, such as the RGD tripeptide, has resulted in an inability to precisely control cellular responses. To overcome this limitation, we conducted multiple replications of the integrin α2β1-specific ligand, the collagen hexapeptide Gly-Phe-Pro-Gly-Glu-Arg (GFPGER) in Pichia pastoris. This enabled the development of recombinant collagen with high biological activity, which was subsequently expressed, isolated, and purified for structural and functional analysis. The proteins carrying the multiple replications GFPGER sequence demonstrated significant bioactivity in cells, leading to enhanced cell adhesion, osteoblast differentiation, and mineralization when compared to control groups. Importantly, these effects were mediated by integrin α2β1. The new collagen constructed in this study is expected to be a biomaterial for regulating specific cell functions and fates.

Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice

Lysosomal galactosylceramidase (GALC) is expressed in all brain cells including oligodendrocytes (OLs), microglia and astrocytes, though the cell-specific function of GALC is largely unknown. Mutations in GALC cause Krabbe disease, a fatal neurological lysosomal storage disorder that usually affects infants. To study how Galc ablation in each glial cell type contributes to Krabbe pathogenesis, we used conditional Galc floxed mice. Here, we found that OL-specific Galc conditional knockout (CKO) in mice results in a phenotype that includes wasting, psychosine accumulation, and neuroinflammation. Microglia- or astrocyte-specific Galc deletion alone in mice did not show any specific phenotypes. Interestingly, mice with CKO of Galc from both OLs and microglia have a more severe neuroinflammation with an increase in globoid cell accumulation than OL-specific CKO alone. Moreover, the enhanced phenotype occurred without additional accumulation of psychosine. Further studies revealed that Galc-KO microglia cocultured with Galc-KO OLs elicits globoid cell formation and the overexpression of osteopontin and MCP-1, both proteins are known to recruit immune cells and promote engulfment of debris and damaged cells. We conclude that OLs are the primary cells that initiate KD with an elevated psychosine level and microglia are required for the progression of neuroinflammation in a psychosine independent manner.

Histological and single-nucleus transcriptome analyses reveal the specialized functions of ligular sclerenchyma cells and key regulators of leaf angle in maize

Leaf angle (LA) is a crucial factor that affects planting density and yield in maize. However, the regulatory mechanisms underlying LA formation remain largely unknown. In this study, we performed a comparative histological analysis of the ligular region across various maize inbred lines and revealed that LA is significantly influenced by a two-step regulatory process involving initial cell elongation followed by subsequent lignification in the ligular adaxial sclerenchyma cells (SCs). Subsequently, we performed both bulk and single-nucleus RNA sequencing, generated a comprehensive transcriptomic atlas of the ligular region, and identified numerous genes enriched in the hypodermal cells that may influence their specialization into SCs. Furthermore, we functionally characterized two genes encoding atypical basic-helix–loop–helix (bHLH) transcription factors, bHLH30 and its homolog bHLH155, which are highly expressed in the elongated adaxial cells. Genetic analyses revealed that bHLH30 and bHLH155 positively regulate LA expansion, and molecular experiments demonstrated their ability to activate the transcription of genes involved in cell elongation and lignification of SCs. These findings highlight the specialized functions of ligular adaxial SCs in LA regulation by restricting further extension of ligular cells and enhancing mechanical strength. The transcriptomic atlas of the ligular region at single-nucleus resolution not only deepens our understanding of LA regulation but also enables identification of numerous potential targets for optimizing plant architecture in modern maize breeding.

In Situ Engineering Cancer Mask to Immobilize Tumor Cells and Block Metastasis.

This work reports a new concept of cancer mask in situ to alter the specific biological functions of cancer cells. Metastatic cancer cells are highly invasive in part due to the presence of the glycan matrix in the cell membrane. Using a rational designed bio-orthogonal reaction, the cancer cell surface is reconstructed in situ by incorporating endogenous polysialic acids in the glycan matrix on the cell membrane to form a mesh-like network, called cancer mask. The network of the glycan matrix can not only immobilize cancer cells but also effectively block the stimulation of metastasis promoters to tumor cells and inhibit the formation of epithelial to mesenchymal transition (EMT), causing metastatic cancer cells incarceration. The results demonstrate a new strategy to control and even eliminate the cancer metastasis that is a major cause of treatment failure and poor patient outcome.

Elucidating the Transcriptional Role of the Nuclear Receptor RORα in CD8+ T Cell Memory vs Effector Cell Development

Abstract CD8+ T cells play a critical role in controlling viral infections and cancer and have the potential to be harnessed for the development of new therapeutic strategies. Defining the transcriptional regulatory networks that control CD8+ T cell differentiation and function is of great importance to achieve these goals. The retinoic acid receptor-related orphan receptor alpha (RORα), a member of the nuclear receptor superfamily of ligand-regulated transcription factors, has emerged as a potential transcriptional regulator of CD8+ T cell immunity. However, exactly how RORα functions in these processes is poorly understood. To this end we seek to identify the transcriptional role of RORα in regulating the differentiation of memory CD8+ T cells. Utilizing a mouse model with T cell-specific deletion of RORα we identify that RORα deficiency in CD8+ T cells leads to increased IFNγ production and increased cell-specific cytolytic function in vitro. Conversely, RORα overexpression results in decreased IFNγ production and defects in proliferative capacity in vitro. Our in vivo data further reveals that deletion of RORα in CD8+ T cells may affect the trafficking of these cells to non-lymphoid tissue and play a role in the development of tissue resident memory (TRM) cells. Our study provides important insights into the role of RORα in regulating CD8+ T cell function and highlights the potential for targeting nuclear receptors in the development of novel cell-based therapeutics.

Cryopreservation and Rapid Recovery of Differentiated Intestinal Epithelial Barrier Cells at Complex Transwell Interfaces Is Enabled by Chemically Induced Ice Nucleation.

Cell-based models, such as organ-on-chips, can replace and inform in vivo (animal) studies for drug discovery, toxicology, and biomedical science, but most cannot be banked "ready to use" as they do not survive conventional cryopreservation with DMSO alone. Here, we demonstrate how macromolecular ice nucleators enable the successful cryopreservation of epithelial intestinal models supported upon the interface of transwells, allowing recovery of function in just 7 days post-thaw directly from the freezer, compared to 21 days from conventional suspension cryopreservation. Caco-2 cells and Caco-2/HT29-MTX cocultures are cryopreserved on transwell inserts, with chemically induced ice nucleation at warmer temperatures resulting in increased cell viability but crucially retaining the complex cellular adhesion on the transwell insert interfaces, which other cryoprotectants do not. Trans-epithelial electrical resistance measurements, confocal microscopy, histology, and whole-cell proteomics demonstrated the rapid recovery of differentiated cell function, including the formation of tight junctions. Lucifer yellow permeability assays confirmed that the barrier functions of the cells were intact. This work will help solve the long-standing problem of transwell tissue barrier model storage, facilitating access to advanced predictive cellular models. This is underpinned by precise control of the nucleation temperature, addressing a crucial biophysical mode of damage.

Cell-type specific effects of mineralocorticoid receptor gene expression suggest intercellular communication regulating fibrosis in skeletal muscle disease.

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD is caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles of myofiber degeneration and regeneration. Pathology is exacerbated by overactivation of infiltrating immune cells and fibroblasts, which leads to chronic inflammation and fibrosis. Mineralocorticoid receptors (MR), a type of nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on DMD cardiomyopathy and preclinical efficacy on skeletal muscle in DMD models. Methods: We have previously generated myofiber and myeloid MR knockout mouse models to dissect cell-specific functions of MR within dystrophic muscles. Here, we compared skeletal muscle gene expression from both knockouts to further define cell-type specific signaling downstream from MR. Results: Myeloid MR knockout increased proinflammatory and profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic gene in myeloid MR-knockout skeletal muscle and is a component of fibrosis in dystrophic skeletal muscle. Surprisingly, lysyl oxidase (Lox), canonically a collagen crosslinker, was increased in both MR knockouts, but did not localize to fibrotic regions of skeletal muscle. Lox localized within myofibers, including only a region of quadriceps muscles. Lysyl oxidase like 1 (Loxl1), another Lox family member, was increased only in myeloid MR knockout muscle and localized specifically to fibrotic regions. Discussion: This study suggests that MR signaling in the dystrophic muscle microenvironment involves communication between contributing cell types and modulates inflammatory and fibrotic pathways in muscle disease.

Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.