Biology subjects

Koizumi, H.

Publications and source records attributed to Koizumi, H..

5 recordsLinked to original sources

bioRxiv2026

CD300a Blockade attenuates renal fibrosis by enhancing macrophage efferocytosis and neutrophil MMP9 production

Renal fibrosis represents an irreversible endpoint of chronic kidney disease. Although macrophage efferocytosis regulates the response to acute renal injury, the mechanisms by which early efferocytosis confers long-term protection against chronic fibrosis remain elusive. Here, we show that phagocyte-specific deletion of the inhibitory receptor CD300a (Cd300afl/flLyz2-Cre) mitigates obstructive renal injury and subsequent fibrosis. CD300a deficiency enhanced efferocytosis by tissue-resident macrophages during the early phase of injury, thereby suppressing the release of damage-associated molecular patterns (DAMPs) and TGF-{beta} expression. This early attenuation of the inflammatory microenvironment altered the composition of recruited neutrophils, shifting them from profibrotic SiglecF+ toward non-profibrotic SiglecF- subsets. Furthermore, loss of CD300a cell-autonomously primed neutrophils for enhanced matrix metalloproteinase-9 (MMP9) production upon injury, whereas neutrophil depletion abolished the protective effect of CD300a deficiency. Importantly, administration of a neutralizing anti-CD300a antibody to wild-type mice recapitulated these protective effects, promoting the shift toward SiglecF- neutrophils and significantly attenuating renal fibrosis. Together, our findings identify CD300a as a regulator of early macrophage efferocytosis and neutrophil-derived MMP9 production, and establish pharmacological CD300a blockade as a potential therapeutic strategy for progressive renal fibrosis.

immunology↗

bioRxiv2026

Functional Synaptic Interactions and Inhibitory Circuitry of the PreBötzinger Complex in the Rhythmic Slice

The preBotzinger Complex (preBotC) within the medulla oblongata contains neuronal circuits critical for generating the mammalian respiratory rhythm, but the functional connectivity among its core excitatory and inhibitory populations remains debated. Defining this connectivity requires disentangling synaptic interactions of functionally identified excitatory and inhibitory preBotC neurons with various electrophysiological phenotypes. We applied a novel synaptic conductance inference method to whole-cell recordings from genetically specified VgluT2-expressing (excitatory) and VGAT-expressing (inhibitory) preBotC neurons active in the rhythmic medullary slice in vitro, which contains core inhibitory-excitatory circuitry with an excitatory rhythmogenic kernel. We found that this circuitry consists of a self-exciting inspiratory VgluT2 population coupled to inspiratory and expiratory VGAT populations that interact reciprocally through inhibition. The functional inhibitory connectome is more complex than previously understood. However, compared with functional synaptic interactions inferred from recordings in the preBotC in situ, the neuronal synaptic conductance profiles in the rhythmic slice reveal a functionally reduced inhibitory connectome, characterized by prominent tonic expiratory inhibition and phasic inspiratory inhibition, without the characteristic multiphasic structure in situ. These results indicate that the functional excitatory and inhibitory circuit interactions within the preBotC isolated in vitro, although reduced relative to more intact states in situ, are intrinsically designed to generate coordinated inspiratory and expiratory population activity. Tonic expiratory phase inhibition together with inspiratory phasic inhibition serves to regulate excitability and phase transitions of the excitatory rhythmogenic kernel.

neuroscience↗

bioRxiv2024

Inference technique for the synaptic conductances in rhythmically active networks and application to respiratory central pattern generation circuits

Unraveling synaptic interactions between excitatory and inhibitory interneurons within rhythmic neural circuits, such as central pattern generation (CPG) circuits for rhythmic motor behaviors, is critical for deciphering circuit interactions and functional architecture, which is a major problem for understanding how neural circuits operate. Here we present a general method for extracting and separating patterns of inhibitory and excitatory synaptic conductances at high temporal resolution from single neuronal intracellular recordings in rhythmically active networks. These post-synaptic conductances reflect the combined synaptic inputs from the key interacting neuronal populations and can reveal the functional connectome of the active circuits. To illustrate the applicability of our analytic technique, we employ our method to infer the synaptic conductance profiles in identified rhythmically active interneurons within key microcircuits of the mammalian (mature rat) brainstem respiratory CPG and provide a perspective on how our approach can resolve the functional interactions and circuit organization of these interneuron populations. We demonstrate the versatility of our approach, which can be applied to any other rhythmic circuits where conditions allow for neuronal intracellular recordings.

neuroscience↗

bioRxiv2021

Predictions and experimental tests of a new biophysical model of the mammalian respiratory oscillator

Previously our computational modeling studies (Phillips et al., 2019) proposed that neuronal persistent sodium current (INaP) and calcium-activated non-selective cation current (ICAN) are key biophysical factors that, respectively, generate inspiratory rhythm and burst pattern in the mammalian preBotzinger complex (preBotC) respiratory oscillator. Here, we experimentally tested and confirmed three predictions of the model from new simulations concerning the roles of INaP and ICAN: (1) INaP and ICAN blockade have opposite effects on the relationship between network excitability and preBotC rhythmic activity; (2) INaP is essential for preBotC rhythmogenesis; (3) ICAN is essential for generating the amplitude of rhythmic output but not rhythm generation. These predictions were confirmed via optogenetic manipulations of preBotC network excitability during graded INaP or ICAN blockade by pharmacological manipulations in neonatal mouse slices in vitro. Our results support and advance the hypothesis that INaP and ICAN mechanistically underlie rhythm and inspiratory burst pattern generation, respectively, in the isolated preBotC.

neuroscience↗

bioRxiv2018

Biophysical mechanisms in the mammalian respiratory oscillator re-examined with a new data-driven computational model

An autorhythmic population of excitatory neurons in the brainstem pre-Botzinger complex is a critical component of the mammalian respiratory oscillator. Two intrinsic neuronal biophysical mechanisms--a persistent sodium current (INaP) and a calcium-activated non-selective cationic current (ICAN)--were proposed to individually or in combination generate cellular-and circuit-level oscillations, but their roles are debated without resolution. We re-examined these roles with a new computational model of an excitatory population with randomly distributed INaP and ICAN conductances and synaptic connections. This model robustly reproduces experimental data showing contrary to previous hypotheses, rhythm generation is independent of ICAN activation, which instead determines population activity amplitude. The novel insight is that this occurs when ICAN is primarily activated by neuronal calcium fluxes driven by synaptic mechanisms. Rhythm depends critically on INaP in a subpopulation forming the rhythmogenic kernel. The model explains how the rhythm and amplitude of respiratory oscillations involve distinct biophysical mechanisms.

bioinformatics↗