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583 results on '"Fukaya, Masahiro"'

5. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis

Author

Kang, Shin H, Li, Ying, Fukaya, Masahiro, Lorenzini, Ileana, Cleveland, Don W, Ostrow, Lyle W, Rothstein, Jeffrey D, and Bergles, Dwight E

Subjects
Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research, Multiple Sclerosis, ALS, Stem Cell Research - Nonembryonic - Non-Human, Neurodegenerative, Genetics, Autoimmune Disease, Regenerative Medicine, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyotrophic Lateral Sclerosis, Animals, Animals, Newborn, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Functional Laterality, Humans, Mice, Mice, Transgenic, Motor Cortex, Myelin Sheath, Nerve Degeneration, Nerve Fibers, Myelinated, Nerve Tissue Proteins, Oligodendroglia, Receptor, Platelet-Derived Growth Factor alpha, Regeneration, Spinal Cord, Survival Analysis, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2(+) cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2(+) cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.

Published
2013

21. Synapse formation and clustering of neuroligin-2 in the absence of [GABA.sub.A] receptors

Author

Patrizi, Annarita, Scelfo, Bibiana, Viltono, Laura, Briatore, Federica, Fukaya, Masahiro, Watanabe, Masahiko, Strata, Piergiorgio, Varoqueaux, Frederique, Brose, Nils, Fritschy, Jean-Marc, and Sassoe-Pognetto, Marco

Subjects
Synapses -- Properties, GABA -- Physiological aspects, Neurophysiology -- Research, GABA -- Receptors, GABA -- Properties, Science and technology
Abstract

GABAergic synapses are crucial for brain function, but the mechanisms underlying inhibitory synaptogenesis are unclear. Here, we show that postnatal Purkinje cells (PCs) of [GABA.sub.A][alpha]1 knockout (KO) mice express transiently the [alpha]3 subunit, leading to the assembly of functional [GABA.sub.A] receptors and initial normal formation of inhibitory synapses, that are retained until adulthood. Subsequently, down-regulation of the [alpha]3 subunit causes a complete loss of GABAergic postsynaptic currents, resulting in a decreased rate of inhibitory synaptogenesis and formation of mismatched synapses between GABAergic axons and PC spines. Notably, the postsynaptic adhesion molecule neuroligin-2 (NL2) is correctly targeted to inhibitory synapses lacking [GABA.sub.A] receptors and the scaffold molecule gephyrin, but is absent from mismatched synapses, despite innervation by GABAergic axons. Our data indicate that [GABA.sub.A] receptors are dispensable for synapse formation and maintenance and for targeting NL2 to inhibitory synapses. However, GABAergic signaling appears to be crucial for activity-dependent regulation of synapse density during neuronal maturation. gephyrin | Purkinje cell | synaptogenesis

Published
2008

40. New Features on the Expression and Trafficking of mGluR1 Splice Variants Exposed by Two Novel Mutant Mouse Lines

Author

Naito, Rika, Kassai, Hidetoshi, Sakai, Yusuke, Schönherr, Sabine, Fukaya, Masahiro, Schwarzer, Christoph, Sakagami, Hiroyuki, Nakao, Kazuki, Aiba, Atsu, and Ferraguti, Francesco

Subjects
cerebellum, electron microscopy, trafficking, glutamate, G protein-coupled receptor, CRISPR/Cas9, Neuroscience, Original Research
Abstract

Metabotropic glutamate receptors (mGluRs) couple to G-proteins to modulate slow synaptic transmission via intracellular second messengers. The first cloned mGluR, mGluR1, regulates motor coordination, synaptic plasticity and synapse elimination. mGluR1 undergoes alternative splicing giving rise to four translated variants that differ in their intracellular C-terminal domains. Our current knowledge about mGluR1 relates almost entirely to the long mGluR1α isoform, whereas little is known about the other shorter variants. To study the expression of mGluR1γ, we have generated by means of the CRISPR/Cas9 system a new knock-in (KI) mouse line in which the C-terminus of this variant carries two short tags. Using this mouse line, we could establish that mGluR1γ is either untranslated or in amounts that are undetectable in the mouse cerebellum, indicating that only mGluR1α and mGluR1β are present and active at cerebellar synapses. The trafficking and function of mGluR1 appear strongly influenced by adaptor proteins such as long Homers that bind to the C-terminus of mGluR1α. We generated a second transgenic (Tg) mouse line in which mGluR1α carries a point mutation in its Homer binding domain and studied whether disruption of this interaction influenced mGluR1 subcellular localization at cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses by means of the freeze-fracture replica immunolabeling technique. These Tg animals did not show any overt behavioral phenotype, and despite the typical mGluR1 perisynaptic distribution was not significantly changed, we observed a higher probability of intrasynaptic diffusion suggesting that long Homers regulate the lateral mobility of mGluR1. We extended our ultrastructural analysis to other mouse lines in which only one mGluR1 variant was reintroduced in PC of mGluR1-knock out (KO) mice. This work revealed that mGluR1α preferentially accumulates closer to the edge of the postsynaptic density (PSD), whereas mGluR1β has a less pronounced perijunctional distribution and, in the absence of mGluR1α, its trafficking to the plasma membrane is impaired with an accumulation in intracellular organelles. In conclusion, our study sets several firm points on largely disputed matters, namely expression of mGluR1γ and role of the C-terminal domain of mGluR1 splice variants on their perisynaptic clustering.

Published
2018

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