Biology subjects

Nitta, N.

Publications and source records attributed to Nitta, N..

5 recordsLinked to original sources

bioRxiv2025

Pharmacological potentiation of Nav1.1 channels in interneurons mitigates tau depositions and neuronal death in a mouse model of neurodegenerative dementias

Epileptiform discharges and neuronal hyperexcitability are key pathophysiological features of Alzheimers disease and related tauopathies. We previously identified selective dynfuntion of parvalbumin-positive GABAergic interneurons (PV neurons), which regulate neural network excitability, in a tauopathy mouse model. However, the mechanistic link between PV neuron deficits, tau pathology, and neurodegeneration remains unclear. Here, we demonstrate that pharmacological enhancement of phasic PV neuron activity markedly attenuates tau accumulation and neuronal loss in a tauopathy mouse model. We developed DSR-143630, a novel activator of voltage-gated sodium channel Nav1.1, selectively expressed in PV neurons. Administration of DSR-143630 alleviated febrile seizures in Nav1.1 haploinsufficient mice and suppressed high-frequency oscillations (HFOs), an electrophysiological signature of hyperexcitability associated with cognitive impairments, in rTg4510 tau transgenic mice. Longitudinal tau PET and volumetric MRI demonstrated that DSR-143630 treatment from 4 to 11 months of age profoundly reduced age-dependent tau deposition and atrophy in the neocortex and hippocampus. Postmortem analyses further revealed decreased levels of phosphorylated tau, preservation of neuronal populations, and attenuated neuroinflammatory responses, including reactive gliosis. These findings establish PV neuron dysfunctions and consequent network hyperexcitability as key drivers of tau pathogenesis and highlight pharmacological Nav1.1 activation as a promising disease-modifying strategy for neurodegenerative tauopathies. One Sentence SummaryPharmacological potentiation of interneuronal activities attenuates aberrant network excitability, progressive tau deposition, and neurodegeneration.

neuroscience↗

bioRxiv2024

Super homotypic targeting by exosome surface engineering

Homotypic targeting is the inherent ability of cells for preferential interaction with cells of similar or identical types, a phenomenon commonly seen in cell adhesion, tissue formation, and immune responses. Unfortunately, its full potential remains largely untapped. Here we introduce an approach to drastically boost the homotypic targeting capabilities of cells via exosomes (nanoscale extracellular vesicles secreted by cells). By engineering exosome surfaces with lanthanides, we amplify specific cell-exosome interactions by more than 25-fold, significantly accelerating the selective capture of exosomes by cells of the same lineage. This substantial enhancement in cellular homophilicity opens up an entirely new class of applications, two of which we showcase here with unprecedented performance: using cells to detect specific exosomes and using exosomes to detect specific cells. The concept of "super homotypic targeting" offers enormous potential to transform cancer diagnostics, immunotherapy, targeted drug delivery, tissue engineering, and vaccine development.

cell biology↗

bioRxiv2022

Distribution of intraperitoneally administered D2O in AQP4-knockout mouse brain after MCA occlusion

As the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain. In this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery. Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI. D2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both contralateral and ipsilateral ACA region compared to wild-type mice. Also, only the AQP4-ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice. These results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo. HighlightsO_LIThe measurement of brain water dynamics with D2O. C_LIO_LIIn vivo investigation of AQP4 loss and focal brain ischemia. C_LIO_LIAQP4 loss affects water dynamics in the ACA region not only in the infarct region. C_LI

physiology↗

bioRxiv2021

Quantitative Measurement of Diffusion-weighted Imaging Signal Using Expression-controlled Aquaporin-4 Cells: Comparative Study of 2-compartment and Diffusion Kurtosis Imaging Models

PurposeThe purpose of this study was to compare parameter estimates for the 2-compartment (2Comp) and diffusion kurtosis imaging (DKm) models obtained from diffusion-weighted imaging (DWI) of aquaporin-4 (AQP4) expression-controlled cells, and to look for biomarkers that indicate differences in the cell membrane water permeability. MethodsDWI was performed on AQP4-expressing and non-expressing cells and the signal was analyzed with the 2Comp and DKm models. For the 2Comp model, the diffusion coefficients (Df, Ds) and volume fractions (Ff, Fs, Ff=1-Fs) of the fast and slow compartments were estimated. For the DKm model, estimates of the diffusion kurtosis (K) and corrected diffusion coefficient (D) were obtained. ResultsFor the 2Comp model, Ds and Fs showed clear differences between AQP4-expressing and non-expressing cells. Fs was also sensitive to cell density. There was no clear relationship with the cell type for the DKm parameters. ConclusionsChanges to cell membrane water permeability due to AQP4 expression affected DWI of cell suspensions. For the 2Comp and DKm models, Ds was the parameter most sensitive to differences in AQP4 expression.

cell biology↗

bioRxiv2020

MRS-measured Glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We also assessed regional neurochemical and functional statuses related to spontaneous neural firing by measuring MRS signals and neuronal activities in a mouse model of Dravet syndrome under a resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that the MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

neuroscience↗