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Now showing items 1 - 16 of 31

  • Microglia as possible therapeutic targets for autism spectrum disorders.

    Andoh, Megumi   Ikegaya, Yuji   Koyama, Ryuta  

    Malfunctions of the nervous and immune systems are now recognized to be fundamental causes of autism spectrum disorders (ASDs). Studies have suggested that the brain's resident immune cells, microglia are possible key players in ASDs. Specifically, deficits in synaptic pruning by microglia may underlie the pathogenesis of ASDs, in which excess synapses are occasionally reported. This idea has driven researchers to investigate causal links between microglial dysfunction and ASDs. In this review, we first introduce the characteristics of microglia in ASD brains and discuss their possible roles in the pathogenesis of ASDs. We also refer to immunomodulatory agents that could be potentially used as symptomatic therapies for ASDs in light of their ability to modify microglial functions. Finally, we will mention a possible strategy to radically cure some of the symptoms reported in ASDs through reorganizing neural circuits via microglia-dependent synaptic pruning. =C2=A9 2019 Elsevier Inc. All rights reserved.
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  • Neonatal Seizure Models to Study Epileptogenesis

    Kasahara, Yuka   Ikegaya, Yuji   Koyama, Ryuta  

    Current therapeutic strategies for epilepsy include anti-epileptic drugs and surgical treatments that are mainly focused on the suppression of existing seizures rather than the occurrence of the first spontaneous seizure. These symptomatic treatments help a certain proportion of patients, but these strategies are not intended to clarify the cellular and molecular mechanisms underlying the primary process of epilepsy development, i.e., epileptogenesis. Epileptogenic changes include reorganization of neural and glial circuits, resulting in the formation of an epileptogenic focus. To achieve the goal of developing "anti-epileptogenic" drugs, we need to clarify the step-by-step mechanisms underlying epileptogenesis for patients whose seizures are not controllable with existing "anti-epileptic" drugs. Epileptogenesis has been studied using animal models of neonatal seizures because such models are useful for studying the latent period before the occurrence of spontaneous seizures and the lowering of the seizure threshold. Further, neonatal seizure models are generally easy to handle and can be applied for in vitro studies because cells in the neonatal brain are suitable for culture. Here, we review two animal models of neonatal seizures for studying epileptogenesis and discuss their features, specifically focusing on hypoxia-ischemia (HI)-induced seizures and febrile seizures (FSs). Studying these models will contribute to identifying the potential therapeutic targets and biomarkers of epileptogenesis.
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  • The Astrocytic cAMP Pathway in Health and Disease

    Zhou, Zhiwen   Ikegaya, Yuji   Koyama, Ryuta  

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  • The Astrocytic cAMP Pathway in Health and Disease.

    Zhou, Zhiwen   Ikegaya, Yuji   Koyama, Ryuta  

    Astrocytes are major glial cells that play critical roles in brain homeostasis. Abnormalities in astrocytic functions can lead to brain disorders. Astrocytes also respond to injury and disease through gliosis and immune activation, which can be both protective and detrimental. Thus, it is essential to elucidate the function of astrocytes in order to understand the physiology of the brain to develop therapeutic strategies against brain diseases. Cyclic adenosine monophosphate (cAMP) is a major second messenger that triggers various downstream cellular machinery in a wide variety of cells. The functions of astrocytes have also been suggested as being regulated by cAMP. Here, we summarize the possible roles of cAMP signaling in regulating the functions of astrocytes. Specifically, we introduce the ways in which cAMP pathways are involved in astrocyte functions, including (1) energy supply, (2) maintenance of the extracellular environment, (3) immune response, and (4) a potential role as a provider of trophic factors, and we discuss how these cAMP-regulated processes can affect brain functions in health and disease.=20
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  • Microglia in the pathogenesis of autism spectrum disorders

    Koyama, Ryuta   Ikegaya, Yuji  

    Highlights • We discussed the possible involvement of microglia in the pathogenesis of ASD. • Impairments in synapse E/I balance in ASD are discussed. • The characteristics of microglia in ASD are discussed. • The role of the hippocampus in ASD is discussed. Abstract Proper synaptic pruning is essential for the development of functional neural circuits. Impairments in synaptic pruning disrupt the excitatory versus inhibitory balance (E/I balance) of synapses, which may cause neurodevelopmental disorders such as autism spectrum disorder (ASD). Recent studies have determined molecular mechanisms by which microglia, the brain's resident immune cells, engulf inappropriate and less active synapses. Thus, microglial dysfunction may be involved in the pathogenesis of ASD through attenuated or excess synaptic pruning. In this review, we discuss recent animal and human studies that report an E/I imbalance and the characteristics of microglia in ASD. We will further discuss whether and how synaptic pruning by microglia is involved in the pathogenesis of ASD.
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  • Dentate Circuitry as a Model to Study Epileptogenesis

    Koyama, Ryuta  

    Epileptogenesis, which can be initiated by brain insults or gene mutations in the normal brain, is defined as the gradual (months to years) process of epilepsy development that begins before the first epileptic seizure. Epileptogenic changes include induction of immediate early genes, post-translational modification of ion-channel functions, neuronal death, gliosis, and reorganization of neural circuits. Each of these changes alone or in combination can contribute to an epileptogenic focus, which is defined by the minimal cortical region that is necessary and sufficient to induce synchronized epileptic bursting activity in neurons. Therefore to discover and develop anti-epileptogenic drugs it is essential to unveil the cellular and molecular mechanisms underlying the development of epileptogenic foci. Among the epileptogenic changes, abnormally appended excitatory recurrent circuits can directly cause synchronized bursting of neuron activity. Here, I will introduce and discuss the mechanisms underlying the development of two representative abnormal neural circuits, namely, hippocampal mossy fiber sprouting and ectopic granule cells, which are found in the dentate gyrus of patients with mesial temporal lobe epilepsy and its animal models. =20
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  • Exercise Reverses Behavioral and Synaptic Abnormalities after Maternal Inflammation

    Andoh, Megumi   Shibata, Kazuki   Okamoto, Kazuki   Onodera, Junya   Morishita, Kohei   Miura, Yuki   Ikegaya, Yuji   Koyama, Ryuta  

    Abnormal behaviors in individuals with neurodevelopmental disorders are generally believed to be irreversible. Here, we show that voluntary wheel running ameliorates the abnormalities in sociability, repetitiveness, and anxiety observed in a mouse model of a neurodevelopmental disorder induced by maternal immune activation (MIA). Exercise activates a portion of dentate granule cells, normalizing the density of hippocampal CA3 synapses, which is excessive in the MIA-affected offspring. The synaptic surplus in the MIA offspring is induced by deficits in synapse engulfment by microglia, which is normalized by exercise through microglial activation. Finally, chemogenetically induced activation of granule cells promotes the engulfment of CA3 synapses. Thus, our study proposes a role of voluntary exercise in the modulation of behavioral and synaptic abnormalities in neurodevelopmental disorders.
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  • The use of organotypic slice cultures for the study of epileptogenesis

    Koyama, Ryuta  

    Epilepsy is a nervous system disorder characterized by recurrent seizures. Among several types of epilepsy, which accounts for a significant portion of the disease worldwide, temporal lobe epilepsy (TLE) is one of the most common types of intractable epilepsy in adulthood. It has been suggested that complex febrile seizures in early life are associated with the development of TLE later in life; however, cellular and molecular links between febrile seizures and TLE remain unclear because of the lack of an appropriate in vitro system. Using rat hippocampal slice cultures, in which many features of native organotypic organization are retained, we found that the dentate granule cells exhibit aberrant migration in the dentate hilus via enhanced excitatory GABA(A) receptor (GABA(A)-R) signaling, which results in granule cell ectopia that persists into adulthood. We further found that the granule cell ectopia is associated with spontaneous limbic seizures in adulthood. Importantly, both of these phenomena were prevented by inhibiting Na(+)K(+)2Cl(-) co-transporter (NKCC1) which mediates the excitatory action of GABA.
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  • Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation

    Hoshi, Yutaka   Okabe, Kohki   Shibasaki, Koji   Funatsu, Takashi   Matsuki, Norio   Ikegaya, Yuji   Koyama, Ryuta  

    Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo. Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia.
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  • Depth and time-dependent heterogeneity of microglia in mouse hippocampal slice cultures

    Kasahara, Yuka   Koyama, Ryuta   Ikegaya, Yuji  

    Microglia are the brain-resident immune cells with the phagocytic capacity to engulf dead and living neurons in health and disease. However, the mechanisms underlying the neuron-microglia interaction remain elusive partly because proper in vitro systems are lacking. Specifically, the highly activated status of microglia with amoeboid morphology in primary culture is different from the 'resting' microglia with multiple processes in vivo. Here, we performed a detailed investigation of microglial properties in mouse hippocampal slice cultures, focusing on the changes in morphology in the activated state, finding a depth and time-dependent localization of in vivo-like microglia in slice cultures. (C) 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
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  • Induced neuronal activity does not attenuate amyloid beta-induced synaptic loss in vitro.

    Kono, Rena   Kim, Gyu Li   Nagata, Hidetaka   Ikegaya, Yuji   Koyama, Ryuta  

    AIM: The accumulation of amyloid beta (Abeta) is one of the characteristics of Alzheimer's disease. The excessive accumulation of Abeta has been suggested to result in a decrease in the number of synapses. Although the number of synapses is generally modulated by neuronal activity, whether neuronal activity affects Abeta-induced synapse loss remains unknown. Therefore, we addressed this question using a primary culture of hippocampal neurons.; METHOD: The neuronal activity of cultured hippocampal neurons from mouse pups was increased using the chemogenetic technique designer receptors exclusively activated by designer drugs (DREADD). The cultured neurons were treated with Abeta, and synapse density was assessed by immunocytochemistry.; RESULTS: Abeta decreased the synapse density probably by decreasing postsynapse. On the other hand, enhanced neuronal activity did not affect the synapse density significantly. However, there was a trend that enhanced neuronal activity increased especially presynapse density.; CONCLUSION: We found that enhanced neuronal activity did not affect Abeta-induced synapse loss in vitro. =C2=A9 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of NeuropsychoPharmacology.
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  • Animal Models for the Study of Human Disease || Experimental Febrile Seizures in Rodents

    Koyama, Ryuta  

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  • Animal Models for the Study of Human Disease || Experimental Febrile Seizures in Rodents

    Koyama, Ryuta  

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  • Long-range axonal calcium sweep induces axon retraction

    Yamada, Ryuji X.   Sasaki, Takuya   Ichikawa, Junya   Koyama, Ryuta   Matsuki, Norio   Ikegaya, Yuji  

    Axon guidance molecules trigger a cascade of local signal in growth cones and evoke various morphologic responses, including axon attraction, repulsion, elongation, and retraction. However, little is known about whether subcellular compartments, other than axonal growth cones, control axon outgrowth. We found that in isolated dentate granule cells, local application of glutamate to the somatodendritic areas, but not the axon itself, induced rapid axon retraction, during which a calcium wave propagated from the somata to the axon terminals. The calcium wave and axon retraction were both inhibited by blockade of voltage-sensitive calcium channels and intracellular calcium dynamics. A combination of perisomatic application of calcium ionophore and depolarizing current injection induced axonal calcium sweep and axon retraction. Thus, perisomatic environments can modulate axon behavior through long-range intracellular communication.
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  • Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

    Schafer, Dorothy P.   Lehrman, Emily K.   Kautzman, Amanda G.   Koyama, Ryuta   Mardinly, Alan R.   Yamasaki, Ryo   Ransohoff, Richard M.   Greenberg, Michael E.   Barres, Ben A.   Stevens, Beth  

    Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.
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  • A Low-Cost Method for Brain Slice Cultures

    Koyama, Ryuta   Muramatsu, Rieko   Sasaki, Takuya   Kimura, Rie   Ueyama, Chihiro   Tamura, Makoto   Tamura, Naohiro   Ichikawa, Junya   Takahashi, Naoya   Usami, Atsushi   Yamada, Maki K.   Matsuki, Norio   Ikegaya, Yuji  

    Low-cost, simple procedures for organotypic tissue cultures are desirable for high-throughput biological experiments such as large-scale medical/drug screening. We present a practical and economical method to cultivate brain slices using hydrophilic filtration membranes. With a cost reduction of more than 90%, this technique allows us to prepare hippocampal slice cultures that are morphologically and functionally indistinguishable from those obtained by the widely used Millicell-CM (R) method.
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