Biology subjects

Haruwaka, K.

Publications and source records attributed to Haruwaka, K..

7 recordsLinked to original sources

bioRxiv2026

Astrocyte-to-microglia purinergic signaling mediates synaptic shielding and promotes neuronal activity

How glial cells sense and regulate neuronal hypoactivity remains poorly understood. Using in vivo imaging in anesthetized, sleeping, and behaving mice, we identified a glial purinergic signaling mechanism that converts neuronal hypoactivity into local circuit regulation. Cortical hypoactivity increased spatially confined ATP release through astrocytic pannexin-1 hemichannels, which were structurally enriched near perisomatic parvalbumin-positive boutons. Local ATP release directed microglial process movement and stabilized bulbous endings through microglial P2Y12 signaling, accompanied by localized Ca{superscript 2} activity in microglial processes. Disruption of astrocytic pannexin-1 or microglial P2Y12 impaired bulbous-ending stabilization and abolished rebound increases in neuronal activity during emergence from anesthesia. Similar ATP release and bulbous-ending formation were observed during chemogenetic neuronal silencing or natural sleep in freely behaving mice. These findings identify astrocyte-to-microglia purinergic signaling as a mechanism that converts neuronal hypoactivity into synapse-selective microglial regulation of circuit activity.

neuroscience↗

bioRxiv2025

Cortical microglia promote noradrenergic signaling to maintain wakefulness

Microglia are essential for maintaining brain homeostasis, including the sleep-wake cycle, but the underlying mechanisms remain unclear. Here, using in vivo two-photon imaging in both head-fixed and freely moving mice with simultaneous electroencephalogram-electromyogram (EEG-EMG) recording, we investigated microglial process dynamics and their interactions with locus coeruleus (LC) noradrenergic (NE) axons in the frontal cortex across sleep-wake states. During sleep or chemogenetic suppression of LC neurons, microglia enhanced their surveillance and increased interactions with NE axons. Correlative electron microscopy at nanometer resolution identified structural contacts between microglial process endings and NE boutons. Mechanistically, microglia-bouton interaction is primed by NE-{beta}2-adrenergic receptor ({beta}2AR) signaling, leading to enhanced Ca{superscript 2} activity in NE axons. These findings suggest that microglial interactions with NE axons promote cortical norepinephrine transmission and maintain stable wakefulness.

neuroscience↗

bioRxiv2025

Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain

Microglia, the primary immune cells of the central nervous system, are known for sculpting excitatory neural circuits via dynamic processes. However, their role in modulating inhibitory synaptic connections in adulthood remains largely unexplored. In this study, we identified an underappreciated microglia subpopulation, satellite microglia with physical soma-soma contact with neurons, that reshape inhibitory circuit connectivity and gate neuronal activity by shielding inhibitory synapses in the adult mouse brain. Using chronic in vivo two-photon imaging in adult mice, we observed in real time that satellite microglia associations displaced perisomatic inhibitory synapses whereas their dissociation permitted inhibitory synaptogenesis. Redistribution of satellite microglia reorganized inhibitory connectivity, altered local neural networks and changed behaviors. These findings establish satellite microglia as key architects of inhibitory circuitry and suggest their broader role in neural plasticity in health and disease.

neuroscience↗

bioRxiv2025

Microglial SWELL1 Deficiency Drives Male-Specific Seizure Vulnerability but Paradoxical Neuroprotection through Impaired Phagocytosis

The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type-specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional knockout (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

neuroscience↗

bioRxiv2024

Impaired microglial phagocytosis promotes seizure development

In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimers disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy. One Sentence SummaryPhagocytic activity of microglia may impact generalized seizure development within both mice and humans.

neuroscience↗

bioRxiv2023

Chemogenetic approaches reveal dual functions of microglia in epilepsy

Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia via of the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that Gi-Dreadd activation can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon {beta} signaling and microglia proliferation. Thus, our findings highlight the importance of microglial activation not only during status epilepticus (SE) but also within later seizure induced pathology.

neuroscience↗

bioRxiv2022

Microglial process dynamics enhance neuronal activity by shielding GABAergic synaptic inputs

Microglia are resident immune cells of the central nervous system (CNS) and play key roles in brain homeostasis. During anesthesia, microglia increase their dynamic process surveillance and interact more closely with neurons. However, the functional significance of microglial process dynamics and neuronal interaction has remained unclear. Using in vivo two-photon imaging in awake mice, we discover that microglia enhance neuronal activity after the cessation of general anesthesia. Hyperactive neuron somata are directly contacted by microglial processes, which specifically co-localize with GABAergic boutons. Electron microscopy-based synaptic reconstruction after two-photon imaging reveals that microglial processes enter into the synaptic cleft to shield GABAergic inputs. Microglial ablation or loss of microglial {beta}2-adrenergic receptors prevent post-anesthesia neuronal hyperactivity. Together, our study demonstrates a previously unappreciated function of microglial process dynamics, which allow microglia to transiently boost neuronal activity by physically shielding inhibitory inputs.

neuroscience↗