Biology subjects

Natesan, S.

Publications and source records attributed to Natesan, S..

14 recordsLinked to original sources

bioRxiv2026

Small Intestinal Submucosa (SIS)-dECM Bioink with Extrusion-Induced Collagen Organization for Tympanic Membrane Tissue Engineering

Tympanic membrane perforations remain a common clinical problem, and although surgical intervention through tympanoplasty achieves high success rates, it is associated with donor-site morbidity, surgical complexity and limited restoration of the native radial and circumferential collagen architecture. In this study, 3D extrusion printing was utilized to create an active scaffold and attempt to promote collagen organization through shear-mediated structural alignment. An alginate-carboxymethyl cellulose (CMC) hydrogel with bovine SIS-dECM was prepared and investigated for its suitability as a bioink alternative to tympanoplasty grafts. The physiochemical, rheological and printability characteristics of the hydrogel were assessed. Successful decellularization was confirmed by histological analysis. The incorporation of the SIS-dECM into the hydrogel led to increased swelling, lower apparent viscosity, yield stress and flow stress while maintaining favourable printability and filament stability. Polarized optical microscopy was also used to study the influence of printing speed on the alignment of collagen to mimic the native tympanic membrane radial collagen architecture. Compared with the cast controls, the printed samples presented stronger birefringence signals. Biological evaluation demonstrated that the 15% dECM hydrogel exhibited the highest live cell area percentage and live/dead ratio after 48 h. In addition, the chick chorioallantoic membrane assay demonstrated that the dECM-containing hydrogels improved vascular density. The findings establish a printable, biologically active dECM bioink capable of generating bulk collagen organization through extrusion printing as a platform for tympanic membrane regeneration.

bioengineering↗

bioRxiv2026

Open-State Dynamics and Allosteric Modulation of the α1β3γ2 GABAA Receptor Stabilized by L9'T/S Substitutions

GABA type A receptors (GABAARs) mediate inhibitory neurotransmission, and their dysfunction contributes to epilepsy, anxiety, and depression. Although closed and desensitized structures of heteropentameric GABAARs are known, an open-state conformation has been difficult to capture. Here we use in-silico mutagenesis and Gaussian-accelerated MD to stabilize open-like ensembles of the 1{beta}3{gamma}2 receptor via hydrophilic substitutions at the hydrophobic 9' gate (L9'T/L9'S). The mutants expand the pore at 9' and 20' (extracellular pore entry), increase hydration and water flux, and lower Cl- permeation barriers at 9' and -2' (desensitization gate) from [~]19/[~]9 kcal mol-{superscript 1} (WT) to [~]1.3-1.6/[~]3.0-3.4 kcal mol-1, yielding ohmic conductance [~]10-30 pS in computational electrophysiology. Conformationally, the mutants show reduced twist, outward M2 tilts, and C-loop closure, consistent with activation-like signatures. On this open-like background, PAMs (diazepam, ganaxolone) primarily tune the residual -2' constriction, whereas bicuculline (orthosteric antagonist) drives a time-ordered, bottom-to-top closing sequence (-2' first, then 9'/20', then twist) via an asymmetric collapse of the M2 bundle that approaches closed-state landmarks while sampling desensitized-like ECD-TMD coupling. Two-electrode voltage clamp confirms spontaneous activity in L9'T-containing receptors, supporting the mutant-stabilized open-like ensembles. These results provide a coherent atomistic framework for gating and allosteric modulation in 1{beta}3{gamma}2 GABAARs and establish a tractable, ligand-responsive platform for state-selective structure-based design.

biophysics↗

bioRxiv2025

Structural Mechanisms Underlying Distinct Binding and Activities of 18:0 and 18:1 Lysophosphatidic acids at LPA1 Receptor

Lysophosphatidic acids (LPAs) are bioactive lipids that regulate numerous physiological functions in humans. Cell signaling by LPAs is mediated mainly via six LPA receptors (LPA1-6), class A G protein-coupled receptors (GPCRs). Among these, LPA1 is recognized to play an essential role in cell proliferation, survival, migration, and tumorigenesis. Despite the structural similarity, 18:0-LPA and 18:1-LPA exhibit distinct functional responses in cell lines overexpressing LPA1. Specifically, our in vitro studies show that 18:1-LPA induces greater Erk activation than 18:0-LPA in PC-3 human prostate cancer cells. The structural basis underlying this differential receptor activation has not been previously studied. Using classical molecular dynamics and enhanced sampling techniques, we examined the access and binding mechanisms of the two LPA species to the active state LPA1 receptor. The results show that 18:0-LPA and 18:1-LPA adopt distinct and dynamic poses in the orthosteric pocket despite their similar starting configurations. Mainly, the alkyl tails of the ligands exhibit distinct orientations and residue interactions, leading to differential conformational changes in key activation switches on the conserved CWxP and PIF structural motifs of the receptor. Also, there are significant differences in interhelical interactions at the intracellular end of the transmembrane helices 1, 3, 6, and 7. These distinct arrangements lead to striking differences in LPA1 interactions with the G-helix of the heterotrimeric Gi-protein. Notably, 18:0-LPA and 18:1-LPA exhibit similar membrane partitioning characteristics and receptor entry processes through aqueous paths. Our comprehensive in-silico studies offer valuable structural insights into the observed differences in functional responses by 18:0-and 18:1-LPA.

biophysics↗

bioRxiv2024

Inhibition of Candida albicans virulence factor by cyclic dipeptides derived from Aeromonas veronii V03

Candida albicans is the most common human fungal pathogen with high mortality rates and limited antifungal treatments. Inhibition of C. albicans pathogenesis by targeting virulence factors provides a promising strategy for the development of novel antifungal drugs and overcoming drug resistance. In this study, four structurally different cyclic dipeptides (or diketopiperazine(DKP) were isolated and identified as cyclo(L-Pro-L-Leu), cyclo(L-Pro-L-Val), cyclo(D-Pro-L-Phe), and cyclo(L-Pro-D-Tyr) from Aeromonas veronii V03 and their antimicrobial potentials were evaluated. Results revealed that identified DKPs exhibited antibacterial activity against bacterial pathogens, such as Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and Aeromonas hydrophila. Importantly, cyclo(D-Pro-L-Phe) lacking hydroxyl groups showed potent inhibitory effects against C. albicans and non-albicans species with low concentrations. Moreover, identified DKPs inhibited the virulence traits of C. albicans, including yeast-to-hyphae transition, secreted hydrolases (aspartic proteases and phospholipase) and biofilm formation in a dose-dependent manner. Collectively, our findings suggest that cyclic dipeptides from DKPs derived from A. veronii V03 could potentially be developed as antivirulence agents against C. albicans infection.

microbiology↗

bioRxiv2024

The relationship between brain activation and mitochondrial complex I protein levels during cognitive function in healthy humans: an BCPP-EF PET and functional MRI study of task switching

Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level dependent (BOLD) response and impairments in cognition. To evaluate the link between mitochondrial complex I, cognition and associated neural activity, 23 cognitively healthy adults underwent a [18F]BCPP-EF PET scan and a functional magnetic resonance imaging (fMRI) scan during which they performed a task switching exercise. We found significant positive associations between [18F]BCPP-EF volume of distribution (VT), which measures mitochondrial complex I levels and the task switching fMRI response (Partial Least Squares (PLS) Canonical Analysis (CA), first component r=0.51, p=0.03). Exploratory Pearsons correlations showed significant positive associations between mitochondrial complex I levels and the fMRI response in regions including the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). Mitochondrial complex I levels across task-relevant regions were also predictive of task switching accuracy (PLS-Regression (PLS-R), R2=0.48, RMSE=0.154, p=0.011) and of switch cost (PLS-R, R^2=0.38, RMSE=0.07, p=0.048). Our findings suggest that higher mitochondrial complex I levels may underlie an individuals ability to exhibit a stronger BOLD response during task switching and are predictive of better task switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction, that should be tested in future studies.

neuroscience↗

bioRxiv2024

Spontaneous brain activity and synaptic density in schizophrenia: a combined UCB-J PET and fMRI study

Schizophrenia is associated with altered Amplitude of Low Frequency Fluctuations (ALFF), a functional Magnetic Resonance Imaging (fMRI) measure of spontaneous brain activity at rest. ALFF in healthy controls has been linked with presynaptic density levels measured by [11C]UCB-J positron emission tomography (PET). Given the growing body of evidence for low presynaptic density levels in schizophrenia, we set out to test if altered [11C]UCB-J binding may be associated with changes in ALFF in schizophrenia, and secondly to test whether the relationships between ALFF and [11C]UCB-J binding differ at the group level. Subjects with schizophrenia had higher ALFF in the medial prefrontal cortex and other regions, in line with published meta-analyses. In control subjects, there was a significant positive relationship between [11C]UCB-J distribution volume ratio (DVRcs) and ALFF in the medial prefrontal cortex (r=0.54, p=0.0365, n=16), but not in subjects with schizophrenia (r=-0.14, p=0.5564, n=22); r-coefficients significantly differed between groups (Zobserved=2.07, p=0.019). At the whole brain level, there were significant positive correlations between [11C]UCB-J DVRcs and ALFF in control subjects in the putamen, insular cortex, precentral gyrus and occipital regions, while in the schizophrenia group, there were significant positive correlations in the bilateral dorsolateral prefrontal cortex and negative correlations in the cuneus, parietal lobule and supramarginal gurus. Correlation coefficients were significantly different between groups across all cortical and subcortical regions with both higher and lower correlation coefficients in the control group. Our results suggest a link between spontaneous brain activity and presynaptic density in control subjects and that this relationship may be disrupted in schizophrenia patients, despite higher ALFF in this group, indicating altered neurobiological mechanisms. Widespread significant differences in ALFF-[11C]UCB-J DVRcs correlation coefficients between controls and schizophrenia subjects highlight the complexity of synaptic dysfunction in schizophrenia and underscore the need for further research to explore the underlying biological mechanisms.

neuroscience↗

bioRxiv2024

Structural basis for the access and binding of resolvin D1 (RvD1) to formyl peptide receptor 2 (FPR2/ALX), a class A GPCR

Inflammation is essential to the bodys defense against tissue injury and microbial invasion. However, uncontrolled inflammation is highly detrimental and can result in chronic inflammatory diseases such as asthma, cancer, obesity, and diabetes. An increasing body of evidence suggests that specialized pro-resolving lipid mediators (SPMs), such as resolvins, are actively involved in critical cellular events that drive the resolution of inflammation and a return to homeostasis. An imbalance caused by insufficient SPMs can result in the unsuccessful resolution of inflammation. The D-series resolvins (metabolites of docosahexaenoic acid), such as resolvin D1 (RvD1) and resolvin D2 (RvD2), carry out their pro-resolving functions by directly binding to class A G protein-coupled receptors FPR2/ALXR and GPR32, and GPR18, respectively. We recently demonstrated that RvD1 and RvD2 preferentially partition and accumulate at the polar headgroup regions of the membrane. However, the mechanistic detail of how RvD1 gains access to the FPR2 binding site from a surrounding membrane environment remains unknown. In this study, we used classical MD and well-tempered metadynamics simulations to examine the structural basis for the access and binding of RvD1 to its target receptor from aqueous and membrane environments. The results offer valuable insights into the access path, potential binding pose, and key residue interactions essential for the access and binding of RvD1 to FPR2/ALXR and may help in identifying small molecule therapeutics as a possible treatment for inflammatory disorders.

biophysics↗

bioRxiv2024

Structural insights into the molecular recognition of integrin αVβ3 by RGD-containing ligands: The role of the specificity-determining loop (SDL)

Integrin V{beta}3 is a prominent member of the "RGD-recognizing" integrin family of cell surface receptors. V{beta}3 binds to various extracellular matrix (ECM) proteins and oxysterols such as 25-hydroxycholesterol, is implicated in several diseases, including cancer metastasis, lung fibrosis, inflammation, and autoimmune diseases, and is pursued as a valuable therapeutic target. Despite enormous efforts to seek a pure antagonist, to date, no single drug candidate has successfully reached clinics due to associated partial agonism and toxicity issues. Developing effective and safe inhibitors require a thorough understanding of the molecular interactions and structural changes related to the receptors activation and inhibition mechanisms. This study offers a comprehensive residue-residue contact and network analyses of the ligand-binding {beta}-propeller {beta}I domains (headpiece) based on all available experimental structures of integrin V{beta}3 in unliganded, agonist-, antagonist-, and antibody-bound states. The analyses reveal many critical interactions that were not reported before and show that specific orientation and interactions of residues from the specificity-determining loop (SDL) are critical in molecular recognition and regulation. Also, the network analysis reveals that residues from the nearby allosteric site (site II) connect to the primary RGD-binding site via SDL, which likely acts as an interface between the two sites. Our results provide valuable insights into molecular interactions, structural changes, distinct features of the active and inactive headpiece conformations, the role of SDL in ligand recognition, and SDL-mediated allostery. Thus, the insights from this study may facilitate the designing of pure antagonists or site II-mediated allosteric modulators to integrin V{beta}3 to treat various diseases.

biophysics↗

bioRxiv2024

Extracellular ISG15 triggers ISGylation via a type-I interferon independent mechanism to regulate host response during virus infection

Type-I interferons (IFN) induce cellular proteins with antiviral activity. One such protein is Interferon Stimulated Gene 15 (ISG15). ISG15 is conjugated to proteins during ISGylation to confer antiviral activity and regulate cellular activities associated with inflammatory and neurodegenerative diseases and cancer. Apart from ISGylation, unconjugated free ISG15 is also released from cells during various conditions, including virus infection. The role of extracellular ISG15 during virus infection was unknown. We show that extracellular ISG15 triggers ISGylation and acts as a soluble antiviral factor to restrict virus infection via an IFN-independent mechanism. Specifically, extracellular ISG15 acts post-translationally to markedly enhance the stability of basal intracellular ISG15 protein levels to support ISGylation. Furthermore, extracellular ISG15 interacts with cell surface integrin (5{beta}1 integrins) molecules via its RGD-like motif to activate the integrin-FAK (Focal Adhesion Kinase) pathway resulting in IFN-independent ISGylation. Thus, our studies have identified extracellular ISG15 protein as a new soluble antiviral factor that confers IFN-independent non-canonical ISGylation via the integrin-FAK pathway by post-translational stabilization of intracellular ISG15 protein.

immunology↗

bioRxiv2024

MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids

BACKGROUNDMYBPC3, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in MYBPC3 by using human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). METHODSThe hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, and functional changes caused by the MYBPC3D389V variant. This variant is associated with increased fractional shortening and is highly prevalent in South Asian descendants. Recombinant C0-C2, N-region of cMyBP-C (wildtype and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro. RESULTSConfocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the MYBPC3D389V variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility with increased contraction velocity, faster calcium cycling, and faster contractile kinetics in hCOs expressing MYBPC3D389V than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in MYBPC3D389V hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential ({Delta}{Psi}m). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after treatment with the myosin inhibitor mavacamten (CAMZYOS(R)) in MYBPC3D389V hCOs. Lastly, various in vitro binding assays revealed a significant loss of affinity in the presence of MYBPC3D389V with myosin S2 region as a likely mechanism for hypercontraction. CONCLUSIONSConceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the MYBPC3D389V hypercontractile phenotype, which was rescued by administration of a myosin inhibitor. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIMYBPC3 mutations have been implicated in hypertrophic cardiomyopathy. C_LIO_LID389V is a polymorphic variant of MYBPC3 predicted to be present in 53000 US South Asians owing to the founder effect. D389V carriers have shown evidence of hyperdynamic heart, and human-induced pluripotent stem cells (hiPSC)-derived cardiomyocytes with D389V show cellular hypertrophy and irregular calcium transients. C_LIO_LIThe molecular mechanism by which the D389V variant develops pathological cardiac dysfunction remains to be conclusively determined. C_LI What New Information Does This Article Contribute?O_LIThe authors leveraged a highly translational cardiac organoid model to explore the role of altered cardiac calcium handling and cardiac contractility as a common pathway leading to pathophysiological phenotypes in patients with early HCM. C_LIO_LIThe MYBPC3D389V-mediated pathological pathway is first studied here by comparing functional properties using three-dimensional cardiac organoids differentiated from hiPSC and determining the presence of hypercontraction. C_LIO_LIOur data demonstrate that faster sarcomere kinetics resulting from lower binding affinity between D389V-mutated cMyBP-C protein and myosin S2, as evidenced by in vitro studies, could cause hypercontractility which was rescued by administration of mavacamten (CAMZYOS(R)), a myosin inhibitor. C_LIO_LIIn addition, hypercontractility causes secondary mitochondrial defects such as higher oxidative stress and lower mitochondrial membrane potential ({Delta}{Psi}m), highlighting a possible early adaptive response to primary sarcomeric changes. C_LIO_LIEarly treatment of MYBPC3D389V carriers with mavacamten may prevent or reduce early HCM-related pathology. C_LI GRAPHICAL ABSTRACTA graphical abstract is available for this article. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/596463v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1489301org.highwire.dtl.DTLVardef@1ab60c1org.highwire.dtl.DTLVardef@5d49d1org.highwire.dtl.DTLVardef@9944d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Unlocking the Role of sMyBP-C: A Key Player in Skeletal Muscle Development and Growth

Skeletal muscle is the largest organ in the body, responsible for gross movement and metabolic regulation. Recently, variants in the MYBPC1 gene have been implicated in a variety of developmental muscle diseases, such as distal arthrogryposis. How MYBPC1 variants cause disease is not well understood. Here, through a collection of novel gene-edited mouse models, we define a critical role for slow myosin binding protein-C (sMyBP-C), encoded by MYBPC1, across muscle development, growth, and maintenance during prenatal, perinatal, postnatal and adult stages. Specifically, Mybpc1 knockout mice exhibited early postnatal lethality and impaired skeletal muscle formation and structure, skeletal deformity, and respiratory failure. Moreover, a conditional knockout of Mybpc1 in perinatal, postnatal and adult stages demonstrates impaired postnatal muscle growth and function secondary to disrupted actomyosin interaction and sarcomere structural integrity. These findings confirm the essential role of sMyBP-C in skeletal muscle and reveal specific functions in both prenatal embryonic musculoskeletal development and postnatal muscle growth and function.

physiology↗

bioRxiv2022

Testing the Drosophila maternal haploid gene for functional divergence and a role in hybrid incompatibility

Crosses between D. simulans females and D. melanogaster males produce viable F1 sons and poorly viable F1 daughters. Unlike most hybrid incompatibilities, this hybrid incompatibility violates Haldanes rule, the observation that incompatibilities preferentially affect the heterogametic sex. Further, it is important to understand fully the genetic basis of this incompatibility because the causal allele in D. melanogaster is a large species-specific block of complex satellite DNA on its X chromosome known as the 359-bp satellite, rather than a protein-coding locus. The causal allele(s) in D. simulans are unknown but likely involve maternally expressed genes or factors since the F1 females die during early embryogenesis. The maternal haploid (mh) gene is an intriguing candidate because it is expressed maternally and its protein product localizes to the 359-bp repeat. We found that this gene has diverged extensively between D. melanogaster and D. simulans. This observation led to the hypothesis that D. melanogaster mh may have co-evolved with the 359-bp repeat, and that hybrid incompatibility thus results from the absence of a co-evolved mh allele in D. simulans. We tested for functional divergence of mh by creating matched transformants of D. melanogaster and D. simulans orthologs in both D. melanogaster and D. simulans strains. Surprisingly, we find that D. simulans mh fully complements the female sterile phenotype of D. melanogaster mh mutations. Contrary to our hypothesis, we find no evidence that adding a D. melanogaster mh gene to D. simulans increases hybrid viability.

evolutionary biology↗

bioRxiv2020

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

The pathophysiology of the majority of neuropsychiatric disorders, including schizophrenia and mood disorders, involves synaptic dysfunction and/or loss, manifesting as lower levels of several presynaptic and postsynaptic marker proteins. Whether chronic exposure to antipsychotic drugs may contribute to this pattern of synaptic loss remains controversial. In contrast, the mood stabiliser lithium has shown to exhibit neurotrophic actions and is thought to enhance synapse formation. Whilst these data are not unequivocal, they suggest that antipsychotic drugs and lithium have contrasting effects on synapse density. We therefore investigated the effect of chronic exposure to lithium and to two different antipsychotics, haloperidol and olanzapine, on presynaptic Synaptic Vesicle glycoprotein 2A (SV2A) and postsynaptic Neuroligin (NLGN) clusters in the rat frontal cortex. Chronic exposure (28 days) to haloperidol (0.5 mg/kg/d) or olanzapine (7.5 mg/kg/d) had no effect on either SV2A or NLGN clusters and no overall effect on synaptic clusters. In contrast, chronic lithium exposure (2 mmol/L eq./d) significantly increased NLGN cluster density as compared to vehicle, but did not affect either SV2A or total synaptic clusters. These data are consistent with and extend our prior work, confirming no effect of either antipsychotics or lithium on SV2A clustering, but suggest contrasting effects of these drugs on the post-synapse. Although caution needs to be exerted when extrapolating results from animals to patients, these data provide clarity with regard to the effect of antipsychotics and lithium on synaptic markers, thus facilitating discrimination of drug from illness effects in human studies of synaptic pathology in psychiatric disorders.

neuroscience↗

bioRxiv2019

Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohens d=2.5, P<0.001) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

neuroscience↗