Biology subjects

Nomura, T.

Publications and source records attributed to Nomura, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Post-intervention high-beta synchronization tracks stable-manifold alignment during stick-balancing learning

Learning to stabilize an unstable object may depend not only on the accuracy of active corrective interventions but also on when to suspend intervention and allow the object's intrinsic dynamics to evolve. We investigated learning-related changes in control dynamics and associated beta-band electroencephalographic (EEG) activity during virtual stick balancing. Ten healthy young adults practiced stabilizing a virtual inverted pendulum with a joystick over two consecutive days; scalp EEG was recorded from seven participants. For each control cycle, control quality was quantified as the distance (dist) between the pendulum state at the end of each active intervention phase and the stable manifold of the control-OFF subsystem. With practice, balance duration increased, dist decreased, and the proportion of time without active intervention increased. Time-frequency responses stratified by control quality showed that post-intervention high-beta event-related synchronization was most prominent in cycles with the smallest dist. Single-cycle linear mixed-effects models further revealed an inverse association between post-intervention high-beta power and dist after accounting for intervention magnitude and movement direction, as well as trial progress where applicable. This relationship was evident in both the initial Control and final Skilled task datasets. These findings indicate that stick-balancing practice improves the ability to terminate active intervention near the stable manifold and suggest that post-intervention high-beta synchronization tracks the quality of the transition from active correction to the intrinsic dynamics of the control-OFF subsystem.

neuroscience↗

bioRxiv2026

Embodied Emergence of Temporal Complexity in Finger Tapping: Synaptic and Dopaminergic Control in Cortico-Basal Ganglia Loops

Finger tapping is a crucial clinical window into the brain's motor integrity, particularly in Parkinson's disease (PD). Beyond mere rhythmicity, healthy motor output exhibits long-range correlations (LRCs)--a hallmark of temporal complexity and physiological adaptability. However, how this fractal structure emerges from the interplay between neural circuits and physical body dynamics, and why it collapses under dopamine depletion, remains elusive. Here, we present an embodied computational model integrating the cortico-basal ganglia-thalamocortical (CBGT) loop with a physical finger model under intermittent control. We demonstrate that LRC is not stochastic noise, but emerges from the interaction between physical finger dynamics and intermittent, sensory-driven action selection. Our simulations reveal that while unbiased action selection yields random variability, a sensory-driven striatal bias generates robust LRC, demonstrating that motor complexity can be actively driven by neural "synaptic bias" rather than passive body mechanics. Crucially, simulating PD pathology via dopamine reduction disrupts this bias, leading to a loss of complexity and white-noise transitions that recapitulate a key qualitative feature of the fractal breakdown observed in PD. By bridging neuromodulation, biomechanical execution, and macroscopic behavior, this work provides a mechanistic framework for embodied neural information processing and offers a potential digital-twin platform for objective biomonitoring in neurodegenerative disorders.

neuroscience↗

bioRxiv2026

Disruption of Histone H4C genes impairs skeletal development and cortical neurogenesis, modeling rare neurodevelopmental syndromes

Histone proteins, which reside in the nuclei of eukaryotic cells, are involved in diverse cellular processes. The core histone H4 serves as a structural component of the nucleosome. Patients carrying mutations in H4Clustered histone (H4C) genes exhibit a broad spectrum of developmental abnormalities, including short stature, microcephaly, intellectual disability, growth retardation, and digital anomalies. However, the impact of H4 mutations on mammalian embryogenesis remains largely unclear. Here, we demonstrate that histone H4C genes play crucial roles in skeletal development and cortical neurogenesis. We found that mRNAs of the histone H4C gene family are specifically expressed in proliferating progenitor cells in the developing mouse neocortex and in human induced pluripotent stem cell-derived cortical organoids. CRISPR-mediated disruption of H4C3 in mice caused severe defects in skeletal formation and neocortical neurogenesis. Furthermore, overexpression of a mutant form of H4C3 resulted in altered expression of genes associated with cellular migration and motility. Together, these findings suggest that histone H4 plays a critical role in regulating the balance between proliferation and differentiation during mammalian embryonic development, thereby explaining the broad spectrum of patient phenotypes.

developmental biology↗

bioRxiv2026

Neural mechanism of postural sway-related beta-band oscillations: a cortico-basal ganglia-thalamic network model of intermittent control

Electroencephalographic (EEG) studies of human quiet stance demonstrate beta-band event-related desynchronization (beta-ERD) during the micro-fall phase of postural sway, followed by event-related synchronization (beta-ERS; post-movement beta rebound) during the micro-recovery phase. These modulations correlate with intermittent ankle muscle inactivation that exploits the stable manifolds of an unstable upright equilibrium; however, the underlying neurocircuit mechanisms remain elusive. Here, we investigated this rhythmogenesis using an embodied spiking neural network model of the cortico-basal ganglia-thalamic (CBGT) circuitry integrated with a physical inverted pendulum. In this closed-loop system, continuous sensory feedback is integrated into the striatum, while the motor cortex executes decisions via drift-diffusion-like population competition, where the decision time (DT) represents the intermittent control-off period. We demonstrate that simulated cortical LFPs exhibit characteristic sway-phase-locked beta-ERD and beta-ERS exclusively when corticostriatal synaptic weights are functionally balanced to implement intermittent control. Conversely, forced-choice continuous control that ceaselessly generates feedback torque fails to replicate these modulations, sustaining flat network states devoid of control-off periods (DT). Structural dissections reveal that while sensory drive remains continuous, sway-phase-locked beta modulations are an emergent property generated fundamentally by bidirectional thalamocortical loops and the intrinsic dynamics of the GPe-STN pacemaker circuit. Our findings suggest that CBGT-mediated, sway-phase-locked beta activity serves as a hallmark of healthy intermittent motor selection. This computational framework provides a crucial bridge linking pathological alterations in basal ganglia dynamics and the loss of behavioral intermittency to the postural impairments observed in clinical populations such as Parkinsons disease. Significance StatementDuring quiet standing, human cortical beta oscillations dynamically modulate in phase with postural sway. Although this phenomenon is heavily linked to healthy motor control, the underlying neural mechanisms have remained unknown. This study resolves this ambiguity by developing a closed-loop computational model combining physical body dynamics with a cortico-basal ganglia-thalamic network. We demonstrate that human-like cortical beta modulations naturally emerge as an architectural property under an intermittent control strategy, driven fundamentally by the GPe-STN pacemaker circuit. Crucially, transitioning to a continuous control regime completely abolishes these oscillations. This framework establishes a direct neurocomputational link between the loss of behavioral intermittency and the pathological degradation of beta-band dynamics observed in patients with Parkinsons disease.

neuroscience↗

bioRxiv2026

Tracing the emergence of the novel fluoroquinolone resistance gene qrtA in enterococci through environmental reservoirs and pELF-type linear plasmids

As animal hosts adapted to land, Enterococcus species diverged from a common ancestor shared with Vagococcus species by acquiring genes essential for survival and transmission in the exposed arid environment. In addition to their intrinsic ruggedness, human-associated enterococci now frequently exhibit multidrug resistance, largely driven by the accumulation of antimicrobial resistance genes (ARGs) on mobile genetic elements (MGEs). However, the source of these resistance elements, their diversity in natural reservoirs, and the risk that they pose remain unclear. To investigate the movement of novel ARGs from the environmental reservoir and the elements that convey them into clinically important enterococcal lineages, we examined environmental vancomycin-resistant enterococci (VRE) circulating in a polluted urban river in Hanoi, Vietnam. Whole-genome sequencing of VRE isolates revealed multidrug-resistance pELF-type linear plasmids harboring a novel fluoroquinolone resistance gene (qrtA) encoding a major facilitator superfamily transporter. The qrtA gene appears to have originated on Vagococcus chromosomes and to have been mobilized by IS1216E-associated MGEs. Vagococcus genomes show strong associations between ARGs, IS1216E, and plasmids related to those in enterococci, and conjugation experiments demonstrated that pELF-type linear plasmids can transfer between Enterococcus and Vagococcus without major fitness costs, positioning them as plausible vehicles for importing environmental ARGs into enterococci. Reconstruction of pELF-type linear plasmid evolution in the environment, together with database mining of rare qrtA-positive clinical isolates from Asia and Europe, suggests that qrtA-bearing pELF-type linear plasmids are in an early phase of global dissemination. These findings highlight the need for coordinated international One Health surveillance of ARG and MGE dynamics, including emerging determinants such as qrtA, together with proactive interventions to limit their spread.

microbiology↗

bioRxiv2026

Digital twins of upright stance reveal mechanistic bifurcations underlying Parkinsonian sway phenotypes

How the central nervous system maintains upright stance--and why this capability collapses in Parkinsons disease (PD)--remains a fundamental open question in computational neuroscience. A primary barrier is a severe topological degeneracy between observable sway kinematics (z-space) and latent neural control policies (-space), causing radically distinct control strategies to mask as identical sway patterns. Here, we establish a dynamical digital twin framework bridging empirical sway time series with mechanistic physical models. Assimilating a large cohort (N = 1, 038) into an intermittent control model via Bayesian inference, we construct a bidirectional mapping (z {leftrightarrow} ) that unmasks these hidden dynamics. We prove that healthy stance is universally governed by flexible intermittent control near an optimal intermittency ratio ({rho} {approx} 0.5), whereas PD progression reflects a structural regression toward rigid continuous control ({rho} [->] 1). Crucially, parameter topology in -space reveals that neural control policies reside on a folded low-dimensional manifold separated by a distinct parameter gap; attractor bifurcation analysis demonstrates that a catastrophic tipping point is embedded within this void, proving that parkinsonian postural breakdown is driven by a discontinuous dynamical phase transition rather than continuous control decay. By unmasking hidden disease severity beneath degenerate sway phenotypes, our framework reframes parkinsonian motor failure as an attractor bifurcation on a neural control manifold, providing a modern computational realization of the classical "dynamical disease" paradigm. SignificancePostural collapse in Parkinsons disease presents a profound neurobiological paradox: cellular degeneration progresses continuously over decades, yet clinical motor failure strikes as a sudden, catastrophic collapse. We resolve this paradox by demonstrating that motor breakdown is not a passive decay of control resources, but a discontinuous dynamical phase transition (attractor bifurcation) triggered when underlying neural control policies cross a latent parameter gap. By unmasking "phenotypic degeneracy"--where radically different neural control strategies produce identical body sway--our digital twin framework redefines neurodegenerative motor failure as a qualitative regime shift in complex control dynamics, offering a universal paradigm for predicting catastrophic transitions in neurological disorders.

neuroscience↗

bioRxiv2026

A pathogenic AMPA receptor gating mutation disrupts synapse-mitochondrion axis and stalls synapse maturation

AMPA receptors (AMPARs) are central regulators of excitatory synaptic transmission and play critical roles in activity-dependent synapse maturation and circuit development. De novo missense mutations in AMPAR subunits have been widely linked to neurodevelopmental disorders (NDDs). Despite this, how these variants lead to neuronal dysfunction remain poorly understood. Here, we investigate the consequences of a recurrent pathogenic mutation in the GluA1 subunit (GRIA1 p.A636T), which alters AMPAR gating properties and is associated with autism spectrum disorder and intellectual disability. We developed a GluA1A636T knock-in mouse model, we show that GluA1A636T mice exhibit impairments in hippocampal-dependent learning and working memory accompanied by reduced baseline activity of CA1 neurons in vivo. Mass spectrometry-based quantitative proteomic analyses of juvenile and adult hippocampal samples revealed that the A636T mutation significantly alters synaptic protein expression at both ages. Notably, the mutation drives a robust upregulation of mitochondrial proteins specifically in adult mice. Consistent with this, dendritic mitochondria in adult GluA1A636T mice exhibited altered morphology and increased oxidative stress. Electrophysiological analyses further revealed abnormalities in synaptic function, including reduced basal excitatory transmission, persistence of functionally silent synapses in adulthood, and altered synaptic plasticity consistent with impaired synapse maturation. Together, these findings demonstrate that a pathogenic AMPAR gating mutation disrupts the coordinated development of synaptic and metabolic programs in the hippocampus, linking altered excitatory signaling to delayed mitochondrial stress and enduring circuit dysfunction. Our study provides a developmental framework for understanding how disease-associated AMPAR variants impair brain function and highlights synapse-mitochondria coupling as a critical axis in glutamate receptor ionotropic (GRI) disorders.

neuroscience↗

bioRxiv2025

Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in Fmr1 Knockout Mice

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the FMR1 gene. Synaptic and circuit-level abnormalities are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons functional, molecular and structural synaptic changes have been described yet the canonical form of Hebbian CA1 long term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was affected in Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming, and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted coupling between NMDA receptors and SK channels in Fmr1 KO mice, which alters the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired adaptive hippocampal learning in Fmr1 KO mice. Significance StatementWhile conventional synaptic plasticity (LTP and LTD) has been extensively examined in Fmr1 KO mice, evidence about the integrity of metaplasticity in these mice has been limited. This study provides a characterization of alterations in NMDA receptor mediated metaplasticity in the hippocampus in Fmr1 KO mice. The question of whether hippocampal LTP is altered in these mice remains unresolved, and changes in metaplasticity may partly explain the discrepancies across studies. Our findings not only identify novel synaptic phenotypes and their underlying mechanisms in the FXS mouse model, but also highlight potential therapeutic targets for FXS.

neuroscience↗

bioRxiv2024

Conserved interhemispheric morphogenesis in amniotes preceded the evolution of the corpus callosum

The corpus callosum (CC) is the large axon bundle connecting the telencephalic hemispheres. The CC is formed exclusively in placental mammals, and the lack of comparable structures in other amniotes obscures the evolutionary origin of the CC. We here demonstrate that interhemispheric remodeling, a prior developmental step for CC formation, is highly conserved in non-mammalian amniotes, such as reptiles and birds. In these animal groups, the spatiotemporal dynamics of interhemispheric remodeling are tightly connected with distinct commissural formations. We observed a high degree of similarity between the mammalian CC and reptilian rostral pallial commissure, (RPC) and significant modifications in the avian pallial projection. Furthermore, we determined that Satb2 plays crucial roles in interhemispheric remodeling, which is associated with proper formation of both the CC and RPC in mice and geckoes, via the use of CRISPR-mediated gene-targeting. Our findings suggest that developmental mechanisms for midline remodeling were already present in the common ancestor of amniotes, which contributed to the evolution of eutherian-specific CC formation.

developmental biology↗

bioRxiv2024

Levetiracetam prevents Aβ42 production through SV2a-dependent modulation of App processing in Alzheimer's disease models

In Alzheimers disease (AD), amyloid-beta (A{beta}) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using App knock-in mouse models of early A{beta} pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of A{beta}42 inside SVs. To explore if targeting SVs modulates A{beta} accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite its mechanism of action being unclear. We discovered Lev reduces A{beta}42 levels by decreasing amyloidogenic processing of APP in a SV2a-dependent manner. Lev corrects SV protein levels and cycling, which results in increased surface localization of APP, where it favors processing via the non-amyloidogenic pathway. Using metabolic stable isotopes and mass spectrometry we confirmed that Lev prevents the production of A{beta}42 in vivo. In transgenic mice with aggressive pathology, electrophysiological and immunofluorescent microscopy analyses revealed that Lev treatment reduces SV cycling and minimizes synapse loss. Finally, we found that human Down syndrome brains with early A{beta} pathology, have elevated levels of presynaptic proteins, confirming a comparable presynaptic deficit in human brains. Taken together, we report a mechanism that highlights the therapeutic potential of Lev to modify the early stages of AD and represent a promising strategy to prevent A{beta}42 pathology before irreversible damage occurs. One Sentence SummaryWe discovered that the SV-binding drug levetiracetam prevents A{beta}42 production by modulating SV cycling which alters APP localization and thus proteolytic processing, highlighting its therapeutic potential for AD.

neuroscience↗

bioRxiv2024

Human and Mouse Models for Kabuki Syndrome Reveal Increase in Inhibitory Synapse Development.

Intellectual disability, affecting 2-3% of the general population, often co-occurs with neurodevelopmental disorders and is frequently caused by mutations that impair synaptic function. Kabuki syndrome (KS), a rare multisystem disorder associated with developmental delay and intellectual disability, results from mutations in either KMT2D (KS1) or KDM6A (KS2), encoding a histone methyltransferase and demethylase, respectively. The mechanisms underlying intellectual disability in KS remain poorly understood. Here, we generated human iPS cells carrying conditional Cre/lox-dependent loss-of-function mutations in KMT2D or KDM6A and differentiated them into excitatory or inhibitory neurons. Analysis revealed that KS1 and KS2 inhibitory neurons unexpectedly showed increased GABAergic synapse formation, whereas excitatory neurons displayed reduced synapse development and impaired synaptic transmission. We confirmed these findings in hippocampal neurons in vitro and in vivo using a mouse model for KS1 demonstrating a bidirectional shift: increase in inhibition and decrease in excitation. Synapse numbers and synaptic transmission in brain slices were shifted to increased inhibition/excitation ratio. Mechanistically, KS1 mutations activated neuroinflammatory signaling, impaired astrocytic function, and promoted glia-driven inhibitory synapse formation in human neurons. By integrating human neuron models with conditional KMT2D/KDM6A deletions and a Kmt2d-mutant mouse model, we identify a novel synaptic disease mechanism in KS that links chromatin remodeling defects to disrupted information transfer in neural circuits, providing a mechanistic explanation for intellectual disability. Significance StatementKabuki syndrome, a rare disorder with intellectual disability, is caused by mutations in the chromatin regulators KMT2D and KDM6A, yet its cellular pathophysiology has remained unclear. Using new Cre/lox-inducible human neuron models together with a mouse model, we reveal a conserved excitation-inhibition imbalance characterized by increased inhibitory and decreased excitatory synapse formation. Our findings establish the first mechanistic framework linking KMT2D/KDM6A mutations to synaptic dysfunction, uncover glial contributions to disease pathogenesis, and suggest potential therapeutic avenues for restoring synaptic balance. HighlightsO_LIKS1 and KS2 mutations cause decrease in excitatory synapses in human neurons C_LIO_LIKS1 and KS2 mutations cause increase in inhibitory synapses in human neurons C_LIO_LIKS1 mutation causes decrease in excitatory and increase in inhibitory synapses in mice C_LIO_LIKS1 mutant mouse astrocytes facilitate increase in inhibitory synapses in human neurons C_LI

neuroscience↗

bioRxiv2024

CD34-positive monocytes are highly susceptible to HIV-1

HIV-1 persists in cellular reservoirs despite effective combined antiretroviral therapy (cART). CD4+ T cells are a well-known reservoir, but there is evidence suggesting that myeloid cells, including circulating monocytes, are also a clinically relevant reservoir. However, it is not fully understood which subsets of monocytes are preferentially infected in vivo. Here, we show that a monocyte fraction expressing a stem cell marker CD34 is more susceptible to HIV-1 infection than the CD34-negative major subset. In cART-untreated viremic individuals, the CD34+ fraction increased in the percentage in total monocytes, and harbored higher copies of proviral DNA than the major subset. Consistent with this, the CD34+ fraction expressed HIV-1 receptors CD4 and CCR5 at higher levels and HIV-1 restriction factors MX2 and SAMHD1 at lower levels. Interestingly, proviral DNA was still detectable in the CD34+ fraction of cART-treated virologically suppressed individuals. CD34+ monocytes were also present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as observed in peripheral blood. Moreover, CD34+ monocytes present in peripheral blood and lymph nodes highly expressed CCR7 and sphingosine-1-phosphate receptor 1 (S1PR1), critical regulators of in vivo cellular trafficking. Collectively, our findings raise the new possibility that lymph node CD34+ monocytes, which originate from the circulation, are infected with HIV-1 owing to their high susceptibility to HIV-1, and return to circulation, which explains the detection of proviral DNA in peripheral CD34+ monocytes even after long-term cART.

immunology↗

bioRxiv2023

Modulation of the spatiotemporal dynamics of striatal direct pathway neurons and motor output by mGluR5

Striatal spiny-projection neurons (SPNs) integrate glutamatergic inputs from the motor cortex and thalamus with neuromodulatory signals to regulate motor output. In vivo Ca2+ imaging has demonstrated that spatially overlapping ensembles of direct and indirect pathway SPNs (dSPNs, iSPNs) are co-active during spontaneous movement. This co-activity is statistically greater among nearby neurons, correlates with behavioral state, and changes in an SPN-type-specific manner under pathological conditions. How this co-activity arises and whether is important for movement are not well understood. Co-activity likely arises from shared excitatory inputs, the strength of which are scaled by well-characterized mechanisms of synaptic plasticity. Here, we show that the Group I metabotropic glutamate receptor 5 (mGluR5), which regulates the strength of corticostriatal synapses, is a key mediator of behaviorally relevant SPN co-activity. Pharmacological modulation of mGluR5 signaling bidirectionally altered movement and co-activity, but not the absolute level of activity in dSPNs. Targeted deletion of mGluR5 in dSPNs recapitulated the effects on spatiotemporal neural dynamics and movement, consistent with a striatum-specific effect of mGluR5 modulation. Targeted deletion of mGluR5 also produced changes in the synaptic properties of dSPNs. Separate from any effects on overall activity, our results show that excitatory synaptic modulation influences motor function by coordinating the spatial co-activation of dSPNs in vivo.

neuroscience↗

bioRxiv2023

A Tetravalent Dengue Virus-like Particle Vaccine Induces High levels of Neutralizing Antibodies and Inhibits Dengue Replication in Non-Human Primates

Dengue virus (DENV) represents a significant global health burden, with 50% of the worlds population at risk of infection, and there is an urgent need for next-generation vaccines. Virus-like particle (VLP)-based vaccines, which mimic the antigenic structure of the authentic virus but lack the viral genome, are an attractive approach. Here we describe a dengue VLP (DENVLP) vaccine which generates a robust and long-lasting neutralizing antibody response against all four DENV serotypes in non-human primates. Importantly, DENVLP vaccination produced no ADE response against any of four DENV serotypes. Finally, we demonstrate in a non-human primate challenge model that DENVLP vaccination substantially reduces viral replication. We also transfer the purified IgG from the immunized monkeys into immunodeficient mice, where they protect against subsequent lethal dengue virus challenge, indicating a humoral mechanism of protection. These results indicate that a DENVLP vaccine is a safe and effective vaccine candidate. One Sentence Summary: Immunization of non-human primates with a tetravalent dengue VLP vaccine induces high levels of neutralizing antibodies and reduces the severity of infection for all four dengue serotypes.

microbiology↗

bioRxiv2023

A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice

Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3R1537C) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.

evolutionary biology↗

bioRxiv2023

A pathogenic missense mutation in kainate receptors elevates dendritic excitability and synaptic integration through dysregulation of SK channels

Numerous rare de novo variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors (iGluRs). However, in many cases it remains unclear how damaging missense variants affect brain function. Here we determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered the equivalent mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, to better understand the human disorder and determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking due to down-regulation of the small conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization (AHP). The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling and lowered the threshold for the induction of LTP of the associational commissural (AC) synapses in the distal dendrites of CA3 neurons. Pharmacological inhibition of SK channels in wild-type (WT) mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.

neuroscience↗

bioRxiv2023

Discrete cortical control during quiet stance revealed by desynchronization and rebound of beta oscillations

Postural sway during quiet stance often exhibits a repetition of micro fall and the subsequent micro recovery. The classical view -that the quiet bipedal stance is stabilized by the ankle joint stiffness- has been challenged by paradoxical non-spring-like behaviors of calf muscles: gastrocnemius muscles are shortened (contract) and then stretched (relax), respectively, during the micro fall and the micro recovery. Here, we examined EEG (electroencephalogram) based brain activity during quiet stance, and identified desynchronization and synchronization of beta oscillations that were associated, respectively, with the micro fall and the micro recovery. Based on a widely accepted scenario for beta-band desynchronization during movement and post-movement rebound in the control of discrete voluntary movement, our results reveal that the beta rebound can be considered as a manifestation of stop command to punctuate the motor control for every fall-recovery cycle. Namely, cortical interventions to the automatic postural control are discrete, rather than continuous modulations. The finding is highly compatible with the intermittent control model, rather than the stiffness control model.

neuroscience↗

bioRxiv2023

Differentiation of Large Extracellular Vesicles in Oral Fluid: Combined Protocol of Small Force Centrifugation and Pattern Analysis

Extracellular vesicles (EVs) in biofluids are highly heterogeneous entities in terms of their origins and physicochemical properties. Considering the application of EVs in diagnostic and therapeutic fields, it is of extreme importance to establish differentiating methods by which focused EV subclasses are operationally defined. Several differentiation protocols have been proposed; however, they have mainly focused on smaller types of EVs, and the heterogeneous nature of large EVs has not yet been fully explored. In this report, to classify large EVs into subgroups based on their physicochemical properties, we have developed a protocol, named EV differentiation by sedimentation patterns (ESP), in which entities in the crude large EV fraction are first moved through a density gradient of iodixanol with small centrifugation forces, and then the migration patterns of molecules through the gradients are analyzed using a non-hierarchical data clustering algorithm. Based on this method, proteins in the large EV fractions of oral fluids clustered into three groups: proteins shared with small EV cargos and enriched in immuno-related proteins (Group 1), proteins involved in energy metabolism and protein synthesis (Group 2), and proteins required for vesicle trafficking (Group 3). These observations indicate that the physiochemical properties of EVs, which are defined through low-speed gradient centrifugation, are well associated with their functions within cells. This protocol enables the detailed subclassification of EV populations that are difficult to differentiate using conventional separation methods.

molecular biology↗