Biology subjects

Mahadevan, V.

Publications and source records attributed to Mahadevan, V..

8 recordsLinked to original sources

bioRxiv2025

Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution.

Decades of studies implicating GluN3A N-methyl-D-aspartate receptor (NMDAR) subunits in physiological and pathological function have largely been interpreted through direct regulation of conventional glutamatergic NMDARs. However, emerging evidence indicates that GluN3A frequently assembles with GluN1 forming unconventional glutamate-insensitive NMDARs that operate as native excitatory glycine receptors (eGlyRs). Here we demonstrate that hippocampal somatostatin and neurogliaform interneurons (Sst-INs and NGFCs) express functional eGlyRs from early postnatal through adult ages. In the developing hippocampus eGlyR-mediated excitation of NGFCs with ambient glycine dramatically increases GABAergic tone, with consequences for the generation of giant depolarizing potentials (GDPs). In the mature hippocampus, eGlyR- mediated excitation of Sst-INs regulates sharp wave ripples (SWRs). Finally, we reveal evolutionary conservation of hippocampal Sst-IN eGlyRs and eGlyR- mediated SWR regulation in non-human primates confirming functional eGlyR availability for therapeutic potential in higher species. Our findings underscore that eGlyR mediated regulation of cell and circuit excitability through both cell autonomous and cell non-autonomous mechanisms must be considered to understand GluN3A roles in brain development, plasticity, and disease.

neuroscience↗

bioRxiv2025

Loss of tumour suppressor p53 rewires enhancer landscape and governs oncogenic progression

Mutations in tumour suppressor p53 confer enhanced metastasis and chemoresistance in colorectal cancer (CRC). Though the genetic events regulating CRC with p53 loss/mutation have been documented, the epigenetic events accompanying the loss of p53 have not been well understood. Epigenome based classification of CRC tumours has identified the active enhancer mark as a distinct marker for progression, however the role of the distal regulatory regions upon p53 loss in CRC remains to be established. This work investigates the influence of p53 loss on enhancer regulation in colorectal cancer cells. Genome wide profiling of active enhancer mark, H3K27ac in p53wt and p53-/- CRC cells reveal an overall gain of this mark around the promoters and intronic regions. These active enhancers show strong association with oncogenes and hallmark MYC and E2F targets suggesting an enhancer mediated regulation of MYC/E2F pathway governed by E2Fs, MAZ and PATZ1. Interestingly, we also observed a gain in oncogenic super enhancers mediated by E2Fs/KLFs accompanying loss of p53. The promoters of histone methyl transferases EZH2 and SuV39H1 (E2F targets) show elevated levels of H3K27ac suggesting a novel epigenetic regulation of CRC around the promoters and distal regulatory regions. Our validation of these findings in p53 deficient colon cancer cohorts shows that the super enhancer associated genes align more to the CMS4 subtype and exhibit lower survivability. The observed cancer stemness and gain of oncogenic super enhancers with p53 loss presents a hitherto unexplored paradigm of enhancer mediated oncogenic progression which may be exploited for devising epigenetic therapy in p53-/- CRC patients. SignificanceColorectal cancers (CRC) lose tumour-suppressor function and gain neomorphic functions with mutation/loss of p53. This work explores the epigenomic modulation of p53 null CRC cells by distal regulatory elements which has not been not clearly understood yet. We report a global increase in the active enhancer mark H3K27ac at active promoter and enhancer regions. We find that the gained enhancers/promoters are regulated by E2Fs/MAZ/PATZ1 which drive cancer stemness while the lost enhancers/promoters are regulated by tumour-suppressive IRFs. The activation of E2Fs correlates with elevated H3K27ac implying positive feedback driving E2F targets such as EZH2 and SuV39H1. The indirect activation of histone methyltransferases by p53 and the gain of oncogenic super-enhancers present a novel epigenetic regulatory paradigm which we also validated in p53 null CRC cohorts. These findings aid the design of epigenetic therapy for p53 deficient colorectal tumours.

genomics↗

bioRxiv2025

Gain of Function p53 mutant R273H confers distinct methylation profiles and consequent partial or full EMT states to colon tumour

p53 is the second most frequently mutated gene in colorectal cancer. While different p53 mutations have been correlated with metastasis, the distinct phenotypes exhibited by site-specific mutations of p53 are not well elucidated. Here, we analyse transcriptomic and methylation data from TCGA-COAD cohort to understand the epigenetic impact of three most prevalent hotspot mutations of p53 (R175H, R273H and R282W). We observed that p53 R273H mutation associates with a partial epithelial-mesenchymal transition (pEMT) state and metastatic progression. In vitro ChIP-seq experiments conducted on p53R27H harbouring HT29 cells revealed an enrichment of mutant p53 R273H at pEMT or mesenchymal gene sets. Further, simulations from a gene regulatory network incorporating the interactions of p53R273H with EMT regulators explain how this mutation shapes the phenotypic landscape accessible to cancer cells. Finally, single-cell transcriptomic analysis of colorectal tumours reveals R273H-linked enrichment of partial and mesenchymal EMT phenotypes across tumour subpopulations in CRC. Overall, we identified distinct epigenetic regulation regulating partial EMT and consequent aggressive behaviour triggered by p53R273H. These findings can help devise effective therapeutic strategies for p53 mutant specific colon tumours. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/662954v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@7d424dorg.highwire.dtl.DTLVardef@18bfcaborg.highwire.dtl.DTLVardef@17950c8org.highwire.dtl.DTLVardef@1a698f9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract CaptionC_FLOATNO Mutation in Tp53 at R273H associates with DNA hypermethylation and elevated pEMT and metastatic signatures as compared to R175 and R282W mutations in colon tumours suggesting of devising novel therapeutic intervention strategies based on p53 mutation profiles. C_FIG

bioinformatics↗

bioRxiv2024

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development

Within the adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting local micro-circuits. However, it is unknown if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not primary neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate early population activity. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

neuroscience↗

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↗

bioRxiv2020

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.

neuroscience↗

bioRxiv2019

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

GABA is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABAA transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABAA transmission can either drive neural activity, or inhibit it through shunting inhibition. The varying roles of depolarizing GABAA transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development, when the majority of synapses form and GABAA transmission switches from depolarizing to hyperpolarizing. Here we addressed the importance of depolarizing but inhibitory (or shunting) GABAA transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABAA transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K+-Cl- co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABAA transmission in CA1 neurons. We found that blocking depolarizing but shunting GABAA transmission increased excitatory synapse number and strength, indicating that depolarizing GABAA transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent, but independent of BDNF signalling. Importantly, the elevated number of synapses was stable for more than a week after GABAA inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABAA transmission in shaping excitatory connectivity during neural circuit development.

neuroscience↗

bioRxiv2017

Native KCC2 Interactome Reveals PACSIN1 As A Critical Regulator Of Synaptic Inhibition

KCC2 is a neuron-specific K+-Cl- cotransporter essential for establishing the Cl- gradient required for hyperpolarizing inhibition. KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to numerous human neurological disorders including epilepsy and neuropathic pain. Using unbiased functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with a diverse set of proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons significantly increases KCC2 expression and hyperpolarizes the reversal potential for Cl-. Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.

neuroscience↗