Hwang, E. M. | bioRxiv Science

bioRxiv2025

MeCP2 regulates cell type-specific functions of depressive-like symptoms in the nucleus accumbens

MeCP2 (methyl CpG binding protein 2) is a transcriptional regulator that modulates gene expression in response to environmental stimuli. Although recent studies have implicated MeCP2 in stress responses and depression, its precise role is not completely understood. In this study, we identify a cell type-specific function of MeCP2 in the regulation of depression-like symptoms within the nucleus accumbens (NAc), a key brain region for emotional and stress processing. We observed differential MeCP2 expression in distinct cell populations of the NAc following chronic restraint stress (CRS) and investigated the behavioral and electrophysiological consequences of cell type-specific MeCP2 manipulation. We also explored the molecular mechanisms by which MeCP2 alleviates depression-like symptoms in the NAc and associated neural circuit regions through cell type-specific profiling of the spatial transcriptome. Our findings demonstrate that MeCP2 contributes to synaptic and circuit-level regulation in a cell type-specific manner within the NAc and ultimately mitigates CRS-induced depression-like behaviors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/666523v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ae5875org.highwire.dtl.DTLVardef@1319231org.highwire.dtl.DTLVardef@174ef60org.highwire.dtl.DTLVardef@fb061_HPS_FORMAT_FIGEXP M_FIG Graphical abstract.Schematic Summary of the functional role of accumbal MeCP2 C_FIG

neuroscience↗

bioRxiv2021

TRPM4 is required for calcium oscillations downstream from the stretch-activated TRPV4 channel

Transduction of mechanical information is influenced by physical, chemical and thermal cues but the molecular mechanisms through which transducer activation shapes temporal signaling remain underexplored. In the present study, electrophysiology, histochemistry and functional imaging were combined with gene silencing and heterologous expression to gain insight into calcium signaling downstream from TRPV4 (Transient Receptor Potential Vanilloid 4), a stretch-activated nonselective cation channel. We show that trabecular meshwork (TM) cells, which employ mechanotransduction to actively regulate intraocular pressure, respond to the TRPV4 agonist GSK1016790A with fluctuations in intracellular Ca2+ concentration ([Ca2+]i) and an increase in [Na+]i. ([Ca2+]i oscillations coincided with a monovalent cation current that was suppressed by BAPTA, Ruthenium Red and 9-phenanthrol, an inhibitor of TRPM4 (Transient Receptor Potential Melastatin 4) channels. Accordingly, TM cells expressed TRPM4 mRNA, protein at the expected 130-150 kDa and showed punctate TRPM4 immunoreactivity at the membrane surface. Genetic silencing of TRPM4 antagonized TRPV4-evoked oscillatory signaling whereas TRPV4 and TRPM4 co-expression in HEK-293 cells reconstituted the oscillations. Membrane potential recordings indicated that TRPM4-dependent oscillations required release of Ca2+ from internal stores. 9-phenanthrol did not affect the outflow facility in mouse eyes. Collectively, our results show that TRPV4 activity initiates dynamic calcium signaling in TM cells by stimulating TRPM4 channels and intracellular Ca2+ release. These findings provide insight into the complexity of membrane-cytosolic interactions during TRPV4 signaling and may foster strategies to promote homeostatic regulation and counter pathological remodeling within the conventional outflow pathway of the mammalian eye.

cell biology↗