Research [Synapse Pathology]
Projects Planned for Research Area
Okazawa Group
| Project Title | Investigation of dynamic synapse pathologies of developmental disorders and neurodegenerative diseases |
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Molecular and functional changes at synapse have attracted attention both in developmental disorders and neurodegenerative diseases. However, the spatiotemporal relationship among disease gene expression, cellular dysfunction, localization and amounts of synapse molecules, and synapse function is not yet identified. In this research, we will try to uncover the relationship by using the virus vector-based in vitro systems in a low-density primary neuron culture and by in vivo imaging of mouse and Drosophila models of developmental disorders and neurodegenerative disease. Through integration of multiple results in such experiments, we will try to clarify dynamic synapse pathologies (molecular pathways from gene to synapse) in developmental disorders and neurodegenerative diseases.
Iwatsubo Group
| Project Title | Pathogenesis and treatment of Alzheimer's disease focusing on the synapses |
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Massive deposition of amyloid β peptide (Aβ) in the brain is the pathological hallmark of Alzheimer disease (AD), although the mechanism of Aβ deposition and neurodegeneration still remains unknown. Based on the recent findings suggesting that Aβ is secreted at synaptic terminals, the idea that AD is a "synaptic disorder", is emerging, whereas there is little evidence directly supporting the notion that synaptic activity influences Aβ secretion and deposition in vivo. In this study, we aim at elucidating (1) the synaptic activity dependent A secretion and deposition in the brains of AD model mice; (2) the molecular mechanism of synaptic activity dependent Aβ secretion; and (3) the mechanism which causes synaptic dysfunction in AD brains, towards the goal of developing a novel therapeutic strategy for AD.
Publicly Invited Research (H25-26)
Hiroyoshi Ariga Group
| Project Title | Regulation of spine formation by DJ-1 through interaction of DJ-1 with Drebrin |
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Dendritic spine plays a role in neurotransmitter transmission in the postsynapse and abnormal spine formation has been reported in various neurodegenerative diseases, especially in diseases with cognitive decline. Long-term depression (LTD) in the synaptic transmission has been observed in DJ-1-knockout mice, suggesting that the reduced level of dopamine becomes a trigger for the LTD. We have found that DJ-1 promotes formation of Drebrin-induced neurite-like projections through direct interaction of DJ-1 with Drebrin, possibly via remodeling of F-actin. In this study, we will analyze the role of DJ-1 in synaptic control under normal and pathogenic conditions, including oxidative stress condition.
Shioda Group
| Project Title | Molecular mechanisms of synapse pathology in ATR-X syndrome. |
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Mental retardation has been constitutively associated with changes in the dendrite arborization and dendritic spine morphology. α-thalassemia X-linked mental retardation (ATR-X) syndrome is a well known X-linked mental retardation showing characterized phenoype with cognitive deficits. Mild mental retardation in ATR-X patients with an Arg37Stop (R37X) mutation in exon 2 is accompanied by reduced expression of ATRX protein. We generated Atrx mutant mice lacking exon 2 (Atrx mice) that show mild learning impairments. In addition, we showed abnormal elevation of CaMKII/Rac1/PAK signaling with concomitant remarkable elongation and thinning of dendritic spines in Atrx mice. However, the mechanism underlying elevated CaMKII activity in these mice remains unclear. Our goal is to define the relevance of molecular mechanisms of synapse pathology in ATR-X syndrome using Atrx mice and ATR-X patients-derived iPS cells.
Yoshida Group
| Project Title | Investigation of synapse pathologies of neurodevelopmental disorders caused by dysfunction of synapse organizers |
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Cell adhesion molecules called "synapse organizers" play a crucial role in neuronal network formation, inducing pre- and postsynaptic differentiation. Mutations in genes encoding synapse organizers as neuroligins (NLGNs) and IL-1 receptor accessory protein-like 1 (IL1RAPL1) are known to lead to intellectual disability and autism. Thus, deregulation of synapse organizer signaling is one of the pathogenic mechanisms of neurodevelopmental disorders. In this research project, we will try to identify the molecular signaling networks downstream of synapse organizers and to clarify the synapse pathologies of neurodevelopmental disorders associated with dysfunction of synapse organizers using proteomic approach and some mouse models.
Kwak Group
| Project Title | Molecular mechanism underlying calcium-permeable AMPA receptor-mediated slow neuronal cell death: implication for ALS |
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In contrast to the normal motor neurons that express only GluA2 (AMPA receptor subunit) with arginine at the glutamine/arginine (Q/R) site (GluA2R), motor neurons of sporadic ALS patients express GluA2 with glutamine at the Q/R site (GluA2Q) due to failure of adenosine to inosine (A-to-I) conversion. A-to-I conversion at the GluA2 Q/R site is specifically mediated by adenosine deaminase acting on RNA 2 (ADAR2) and ADAR2 expression is significantly downregulated in ALS motor neurons. Because motor neurons expressing GluA2Q undergo slow death in conditional ADAR2 knockout mice (AR2) that undergo progressive motor dysfunction, it is likely that failure of GluA2 Q/R site-editing causes death of motor neurons in ALS by the mechanism mediated by Ca2+-permeable AMPA receptors. ADAR2-lacking motor neurons undergo slow death in the conditional ADAR2 knockout mice (AR2) that mimic the molecular abnormality exhibit ALS-like mislocalization of TDP-43 due to cleavage by activated calpain in AR2 mice. Therefore, expression of abnormally Ca2+-permeable AMPA receptors resulting from ADAR2 downregulation is likely a cause of death of motor neurons in ALS. These ALS-like phenotypes of AR2 mice indicate that investigation of molecular mechanism downstream of increased Ca2+ influx through AMPA receptors provide us with a novel insight into the ALS pathogenesis. We found that abnormal vacuoles appear in the nucleus of dying motor neurons and gradually increase in size with the progression of disease in AR2 mice. We focus our investigation on the mechanism whereby the nuclear vacuoles are formed and the role of the nuclear vacuoles in the death cascade of motor neurons.
Watase Group
| Project Title | Elucidating molecular mechanisms underlying neuronal dysfunction caused by mutations in the cytoplasmic tail domain of Cav2.1 channel. |
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Cav2.1 voltage-gated calcium channel gene plays important roles in neurotransmitter release from presynaptic terminals as well as regulation of repetitive firing in Purkinje cells. Deletion of carboxyl-terminal tail part of the channel causes epilepsy accompanied with progressive ataxia whereas expansion of a polyglutamine tract within the same region leads to spinocerebellar ataxia type 6 (SCA6). We have recently generated faithful knock-in mouse models of SCA6 and the mouse exclusively expressing the channel with short cytoplasmic tail domain. Having these models in hand, this group will try to clarify the molecular mechanisms leading to cerebellar synaptic dysfunction and/or degeneration of cerebellar circuits in these conditions and to find candidate targets for therapeutic interventions.
Suzuki Group
| Project Title | Addressing pathological mechanisms by the molecules underlying the central synapse formation, maintenance and plasticity |
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In a neuronal network such as the brain, neurons have to precisely connect to each other, maintain their connections and change their synaptic properties according to their external environment. If something wrong happens to one of these properties, it may result in a severe malfunction such as mental disease. In this study, utilizing highly developed genetic tools in the Drosophila visual system, we embark on identification of a new synaptic organizer in the central synapses, followed by a functional analysis of the protein with a single synapse resolution. We aim for elucidating the molecular pathological mechanisms and establishing the animal model of central synaptic diseases, through revealing molecular mechanisms of (1) the formation, (2)maintenance, and (3) plasticity of central synapses.
Mori Group
| Project Title | DISC1/Neuregulin-1 and synaptogenesis |
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DISC1 would be involved in vesicular transport of various proteins and mRNAs which maintain neuronal function. We found that DISC1 interacts with NRG1 precursor. We have established a new experimental system to quantify the secretion of processed NRG1, resulting that the processed Neuregulin-1 was decreased in cultured hippocampal neuron from DISC1-deficient mice. We aim at clarification of the cause of schizophrenia in the point of synaptogenesis by using DISC1 knockout and NRG1 transgenic mice.
Nakashima Group
| Project Title | Elucidation of mechanisms underlying synapse pathology in neurodevelopmental disorder |
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Mutations in Methyl-DNA biding protein 2 (MECP2) are known to be associated with a variety of neurodevelopmental diseases including, Rett syndrome (RTT), schizophrenia, autism spectrum and bipolar disorder. While these MeCP2-related diseases are likely due to synaptic dysfunction, the direct causative link between MECP2 mutations and synaptic dysfunction has yet to be elucidated. In this study, we will unveil the molecular mechanism of MeCP2 deficiency-induced synaptic dysfunction in neurons based on our finding that MeCP2 modulates post-transcriptional processing of a specific miRNA. Given that MECP2 mutations are associated with various types of neurodevelopmental disorders, our new findings obtained in the present study would shed light on the development of effective therapeutic strategy against these disorders as well.
Kohji Itoh Group
| Project Title | Elucidation of synaptic pathogenesis of neurodegenerative lysosomal storage diseases and application for therapy. |
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Lysosomal storage diseases (LSDs) are inherited metabolic disorders caused by the genetic defect of lysosomal enzymes and related co-factors. Above half of LSDs associate with excessive accumulation of substrates in the central nervous system (CNS) and progressive neurological symptoms. Hence there is no effective therapy for these neurodegenerative LSDs. Our research project is aimed to elucidate the neuropathogenesis and develop novel therapy for LSDs associated with neurological manifestations.
Tay-Sachs disease (TSD) and Sandhoff disease (SD) are GM2 gangliosidoses caused by lysosomal β-hexosaminidase A (HexA, αβ heterodimer) deficiency, associated with excessive accumulation of GM2 ganglioside (GM2) in the CNS. To develop novel intra-cerebrospinal fluid (CSF) enzyme replacement therapy (ERT) for TSD and SD, we had already purified recombinant human HexA produced by methylotrophic yeast as well as modified human HexB with GM2-degrading activity produced by CHO cell line. In this project, in vivo imaging system for replaced enzyme distribution and activity in the brain regions of neurodegenerative SD model mice will be designed and established by use of recombinant human Hex conjugated with pH-activatable fluorescent probe after intra-CSF administration. Change in substrate accumulation including GM2 in the brain regions of SD mice will be also evaluated by imaging mass spectrometry (MS) by means of MS microscopy before and after the intra-CSF administration. The relationship will be also studied between synaptic pathogenesis and specific molecules including cerebellin-1, which may regulate the cerebellar plasticity in the brain of neurodegenerative LSD mice. Furthermore, we would elucidate the molecular bases causing abnormalities in synapse formation and neural circuits among the neuronal cells differentiated from human induced pluripotent stem cells (iPSCs) derived from neurodegenerative LSD patients and molecular mechanism of restoration and normalization after recombinant enzyme replacement.
Sobue Group
| Project Title | Study for the molecular mechanisms underlying stress hormone-induced dysfunction of synaptogenesis and synaptic plasticity |
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Glucocorticoids(GCs) are considered to be one of major stress mediators (stress hormones). Excessive stress hormone exposure, which caused by the stress-induced dysregulation of HPA axis, affects cerebral development, synaptogenesis and synaptic plasticity. These detrimental effects are involved in onset of affective disorders such as depression, anxiety disorder and PTSD. The molecular mechanisms of these stress hormone's effects, however, remain unclear. We have recently found that the stress hormone-induced transient retardation of cerebral development is based on the abnormal neuronal migration via the upregulation of caldesmon, an actin-binding protein. Further, we have established a novel stress hormone-deficit neuronal cell culture system, in which neurons can form synapses. Using this culture system and gene manipulated animals, we will study the molecular mechanisms underlying stress/stress hormone-, as well as epigenetic regulation-induced changes in synaptic plasticity involved in actin cytoskeletal and PSD (postsynaptic density) scaffold proteins.
Fukata Group
| Project Title | Mechanisms for synaptic and circuit dysfunction of familial temporal lobe epilepsy |
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Epilepsy is a common neurological disorder with a high incidence of ~1.0%. However, etiology and pathogenesis of epilepsy are not completely understood, and fundamental strategies for treatment of epilepsy are still awaited. In this study, our group will focus on the epilepsy-related ligand/receptor, LGI1 and ADAM22, which we recently discovered and which plays an essential role in the regulation of brain activity. We will elucidate how epilepsy-associated LGI1 mutations cause abnormal synaptic transmission, and what LGI1 dysfunction has effects on in neural circuits to cause epilepsy; and will develop the therapeutic approach for epilepsy based on the obtained pathogenic mechanism.
Jun Aruga Group
| Project Title | Pathophysiology of myopia and sensory deafness comorbidity caused by synapse formation deficits |
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Myopia and hearing loss are both common sensory disorders. The prevalence of ocular abnormalities in deaf children is high, suggesting the presence of common causal factors. Recently we found that a synaptogenic transmembrane protein-encoding SLITRK6 is a causal gene of myopia and sensorineural deafness. Inner ear and retinal neural circuits contain ribbon synapses which may have been adapted to the perception of the special senses. However, the mechanism underlying their formation has not been fully elucidated. In this study, we clarify the pathophysiology caused by the SLITRK6 deficiency using its knockout mice as disease model animals and the involvement of SLITRK6 in ribbon synapse formation is addressed. The results will be beneficial for better understanding of physiological role of SLITRK family proteins.
Yamagata Group
| Project Title | Regulation of dendritic spine morphology by the autism-related TAO2 kinase |
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We have clarified that the activity-regulated protocadherin arcadlin/PCDH8 induces dendritic spine retraction through acceleration of N-cadherin endocytosis. Arcadlin-associated TAO2 kinase and downstream p38 MAP kinase are necessary for this process. On the other hand, it has been reported that microdeletion and microduplication of human chromosome 16p11.2 is associated with autism complicated with mental retardation and schizophrenia, respectively. Human TAO2 gene is located on this chromosomal region. Therefore, we will investigate whether the arcadlin signal transduction system is involved in the pathogenesis of aberrant spine morphology and behavioral deficits in autism by generating TAO2 knockout mice.
Wada Group
| Project Title | Maternal dietary effects on the functional development of the offspring brain |
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Previously, we observed that high fat diet (HFD) treatment in mice for 12 weeks before pregnancy to the weaning caused the increase of lipid peroxidation and the decrease of neurogenesis and BDNF production in the hippocampus of the young offspring. Besides, we found altered development of the dendrite of newborn neurons and the impaired spatial learning performance in the young offspring. Interestingly, the changes were not detected in the adult offspring when the pups had normal diet after the weaning.
In this joint research program, we reported first that prolonged HFD treatment in the offspring after the weaning caused the decrease of the number of the spines on the hippocampal neurons as well as the medial prefrontal cortex neurons. Turnover rate of the spines was increased in the two area.
As a next step, we are going to study whether the pups with normal diet after the weaning show any alterations at the spine or not. We also plan to identify the factors essentially involved in the alterations. Subsequently, we are going to study whether the spine alteration in the young stage would increase the susceptibility to brain disorders or not in adult mice.
Ichinohe Group
| Project Title | Mechanisms of primate-characteristic developmental synaptic formation and pruning and their dysfunction of developmental disorders |
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Brains of primates including human show rapid increase of their synapses during neonatal and early childhood, and synapse number reaches peak during childhood, and later decreases gradually in life long. Recently, it have been discovered that there is a relationship between psychiatric disease and abnormal synaptic formation patterns. For example, synapses of autism spectrum disorder show faster increase and slow and less pruning, and synapses of schizophrenia show excessive pruning during childhood and puberty. This project aims to elucidate molecular mechanisms of normal primate-characteristic developmental synaptic formation and pruning, and to seek molecular abnormality of synaptic development using autism model marmoset, which we have developed.
Nagai Group
| Project Title | Molecular elucidation of neuronal and synaptic dysfunctions in neurodegenerative diseases |
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Neurodegenerative diseases such as Alzheimer's, Parkinson's, and the polyglutamine diseases are believed to be caused by protein misfolding and aggregation that eventually lead to neuronal dysfunctions, which are suggested to be reversible and hence ideal therapeutic targets. However, the precise mechanisms involved in the protein misfolding-induced neuronal dysfunctions have remained poorly understood. In this study, aiming to elucidate the molecular mechanisms of reversible neuronal dysfunctions in neurodegenerative diseases in vivo, 1) we will analyze synaptic dysfunctions in Drosophila disease models by genetic modifier screening. 2) We will also evaluate time-dependent alterations in synaptic function, microglia-synapse interaction and neuronal network in mouse models of neurodegenerative diseases by two-photon laser scanning microscopy.
Collaborators
Tomita Group
| Project Title | Molecular mechanism of synaptic modulation of secretase activities |
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Deposition of amyloid-beta peptide is implicated in the pathogenesis of Alzheimer disease. Several lines of evidence suggest that enzymatic activity of secretases, which are responsible enzymes for Abeta production, is modulated by synaptic activity. Secretases are also involved in the proteolytic processing of synaptic adhesion molecules that play an important role in synaptic function. However, the molecular relationships between secretase activity and synaptic function still remain unclear. In this project, we will analyze the molecular mechanism as well as the functional significance of synaptic modulation of secretase activities.
Takumi Group
| Project Title | Synaptic pathology of a mouse model of 15q duplication syndrome |
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Autism is a complex psychiatric illness which has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice using chromosome engineering to generate a 6.3-Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display autistic behavioral features. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. In this study we perform morphological analyses at the spine level to understand the molecular pathophysiology of abnormal social behavior.
Uchiyama Group
| Project Title | Protein degradation in axonal compartments and its impairment |
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Different from neuronal somata and dendrites, the degradation system in axonal compartments remains largely unknown. The most important role of the axon is to transfer stimulus to the targets. It has been shown that impairment of autophagy in the axon may explain possible mechanism for axonopathy associated with neurodegeneration. However, molecular mechanism for autophagosome formation in the axonal compartments is largely unknown. To further understand protein degradation through autophagy in axonal compartments we produced transgenic mice expressing Atg9A, DFCP1, and Tom20 that are fused with fluorescence proteins, respectively. Using these mice that express Atg9A, an essential member of autophagosome formation, DFCP1 that relates to the initiation of autophagosome formation, or Tom 20, a receptor for proteins with mitochondrial targeting signal, we try to analyze precise molecular mechanism for autophagosome formation in axonal compartments and its impairment.
Hattori Group
Publicly Invited Research (H23-24)
Shioda Group
| Project Title | Regulation of dendritic spine morphology by protein phosphatase 1/2A in synapse pathology |
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Protein phosphatase (PP)-1 and -2A mainly localized in neuronal nuclei, are related to mental disorder. PP1/2A directly dephosphorylate Ca2+/calmodulin dependent protein kinase II (CaMKII) in nuclei, and regulate genes expression involved in mental disorders. However, physiological and pathological roles of PP1/2A in formation of dendritic spine morphology remain unclear. In this project, we will elucidate regulations of dendritic spine morphology by PP1/2A manipulation of PP1/2A activities in neuronal nuclei as followed. 1) Identification of PP1/2A phosphatases activities in neuronal nuclei, 2) The mechanisms in dendritic spine morphological changes derived from imbalance of PP1/2A and CaMKII activities in neuronal nuclei and 3) Recovery of synapse pathology against abnormal dendritic spine morphology using mental retardation model mice by manipulation of PP1/2A and CaMKII activities in neuronal nuclei. Our goal is to define the relevance of PP1/2A and CaMKII in the dendritic spine formation.
Kwak Group
| Project Title | Investigation of ADAR2 activity in ALS motor neurons |
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GluA2 is a subunit of the AMPA receptor, playing a key role in the regulation of Ca2+ permeability of AMPA receptors; AMPA receptors containing Q/R site-edited GluA2 are Ca2+-impermeable, whereas those containing Q/R site-unedited GluA2 are Ca2+-permeable. Significant proportions of motor neurons of sporadic ALS patients express Q/R site-unedited GluA2 in a disease-specific and lesion-selective manner. Because adenosine deaminase acting on RNA 2 (ADAR2) is the specific RNA editing enzyme at the GluA2 Q/R site and because inability to edit the GluA2 Q/R site is a direct cause of death of motor neurons, ADAR2 downregulation plays a pivotal role in the ALS pathogenesis. In this research project, we investigate the regulatory mechanism of ADAR2 activity in ALS motor neurons.
Mori Group
| Project Title | The role of DISC1/Neuregulin-1 in synapse formation |
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Since the etiological mechanisms of psychiatric disorders such as schizophrenia remain largely esoteric, the promotion of the research for elucidating the pathogenic mechanism has been expected. In this study, we focus on the molecular networks composed of the risk factors of schizophrenia such as DISC1 and Neuregulin-1 to clarify the onset of schizophrenia. Recently, we found that DISC1 could associate with Neuregulin-1 by Affinity Chromatography analysis. We are examining the intracellular function and the involvement of the association in synaptic formation by cell biological experiments. Thereafter, we aim to establish the application to diagnosis and therapy for schizophrenia with in vivo techniques and behavioral pharmacological analyses with DISC1 and Neuregulin-1 mutant mice.
Sobue Group
| Project Title | Study for the molecular mechanism underlying stress hormone-induced dysfunction of synaptogenesis and synaptic plasticity |
|---|
Glucocorticoids(GCs) are well known as one of stress-induced hormones. Excess glucococorticoid exposure, which caused by the stress-induced dysregulation of endocrine homeostasis, affects cerebral development, synaptogenesis and synaptic plasticity. These detrimental effects are involved in onset of affective disorders such as depression, anxiety disorder and PTSD. The molecular mechanisms of these GC’s effects, however, remain unclear. We have recently found that the GC-induced transient retardation of cerebral development is based on the abnormal neuronal migration via the upregulation of caldesmon, an actin-binding protein. Further, we have established a novel GC-deficit neuronal cell culture system, in which neurons can form synapses. Using this culture system, we will study the molecular mechanism underlying stress/GC-induced changes in spine dynamics involved in actin cytoskeletal and PSD (postsynaptic density) scaffold proteins.
Shirane Group
| Project Title | Molecular mechanism of synaptic regulation via endomembrane system |
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Endomembrane system is the network of intracellular organelles. We are studying the endomembrane-related synaptic regulation, which are involved in higher brain function and neurological disorders. Protrudin is suggested to be associated with AMPA receptor transport in dendritic spine via regulation of Rab11-recycling endosome trafficking system. Furthermore, mutation of protrudin has reported in a neurological disorder hereditary spastic paraplegia (HSP), of which etiology is related to membrane curvature. The defects in higher brain function as well as spasticity are symptoms of HSPs. To further elucidate the underlying mechanism of the synaptic regulation associated with these neurological disorders, we will focus on the membrane dynamics through the vesicular trafficking and the membrane curvature.
Matsumoto Group
| Project Title | Isolation of abnormal synapse-related molecules in human neurological disorders |
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To elucidate genes responsible for autosomal recessive spinocerebellar ataxias (ARSCAs) and pediatric epileptic diseases, we recruited three ARSCA families with consanguinity as well as many children with various types of epileptic diseases. Homozygosity mapping by SNP array and exome sequencing by next generation sequencing detected a homozygous mutation in a gene which was possibly synapse-related in one ARSCA family (unpublished). Regarding pediatric epileptic diseases, we isolated a mutation also in a synapse-related gene (unpublished). Functional analysis of these mutations and further molecular searching are underway.
Tomiyama Group
| Project Title | Synaptic and cellular dysfunctions caused by intracellular Aβ oligomers: Possible involvement of tau in the pathology |
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Synaptic and cognitive dysfunctions in Alzheimer’s disease are believed to be caused by extracellular Aβ oligomers. However, it has been shown that intracellular Aβ also contributes to these alterations. We previously demonstrated that intraneuronal accumulation of Aβ oligomers impaired synaptic and cellular functions in transgenic mice expressing APP with the E693Δ mutation. While the toxicity of extracellular Aβ has been shown to depend on tau expression, it is unclear whether tau is involved in the toxicity of intracellular Aβ. To address this question, we decided to investigate the toxicity of intracellular Aβ oligomers in the presence and absence of tau in the APP E693Δ transgenic mice crossed with tau knockout mice or tau transgenic mice. The present study would help to elucidate the mechanism of intracellular Aβ oligomer-induced pathology.
Kobayashi Group
| Project Title | Phenotype change in glutamatergic synapses induced by monoaminergic hyperfunction |
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Dysfunctions of the central monoaminergic system and glutamatergic synapses have been implicated in psychiatric disorders such as schizophrenia and depression. We have recently shown that chronic antidepressant treatments in adult mice can transform the phenotype of mature hippocampal glutamatergic synapses to immature-like one, and also suggested that hyperfunctioning of the monoaminergic modulatory system plays a critical role in this change of the synapse phenotype. Since this effect is correlated with the induction of behavioral abnormalities, the altered synapse phenotype may be related to adverse reactions to antidepressant drugs in humans. In the present project, using this candidate synapse pathology model, we will examine mechanisms underlying the induction and expression of the phenotype change in glutamatergic synapses associated with monoaminergic hyperfunctioning.
Fukata Group
| Project Title | Mechanisms for synaptic and circuit dysfunction of familial temporal lobe epilepsy |
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Epilepsy is a common neurological disorder with a high incidence of ~1.0%. However, etiology and pathogenesis of epilepsy are not completely understood, and fundamental strategies for treatment of epilepsy are very awaited. In this study, I will focus on the epilepsy-related ligand/receptor, LGI1 and ADAM22, which our group recently discovered and which plays an essential role in the normal brain activity. I will elucidate i) how epilepsy-associated LGI1 mutations cause abnormal synaptic transmission, and ii) how dysfunction of hippocampal neural circuits is involved in epileptogenesis.
Yamagata Group
| Project Title | Molecular mechanism of aberrant spine formation in tuberous sclerosis. |
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Tuberous sclerosis complex (TSC) is a phakomatosis, which is frequently comorbid with epilepsy, developmental delay and autism. TSC is caused by mutations in TSC1 or TSC2 genes. Recent studies have demonstrated that TSC2 protein enhances the GTPase of a small G-protein Rheb, which activates the mammalian target of rapamycin (mTOR). In TSC patients, Rheb is converted to GTP-bound form by TSC1 or TSC2 mutation, and consequently activates the mTOR signaling pathway, which causes various neuropsychiatric symptoms. In addition, it has been observed that the TSC neurons exhibit aberrant dendritic spine morphology as well as those in other developmental disorders, including autistic spectrums and mental retardation. In this study, we will explore the molecular mechanism for dendritic spine abnormality in TSC neurons.
Wada Group
| Project Title | Maternal dietary effects on the functional development of the offspring brain |
|---|
There are few molecular studies that have revealed how individual dietary status affects the synaptic function in each person. Previously, we observed that intake of high fat diet (HFD) for 12 weeks before weaning causes some changes in the brain of the offspring. In the young offspring from HFD dams, we detected the increase of lipid peroxidation and the decrease of neurogenesis in the hippocampus, and the impaired spatial learning performance. In this study, we plan to analyze the relationship between maternal dietary status and the function and the morphology changes in the offspring synapses. We are going to analyze the underlying mechanism of the maternal dietary effects on the offspring, and to detect the factors involved in the possible irreversible alterations in the offspring.
Nagai Group
| Project Title | Molecular elucidation of neuronal and synaptic dysfunctions in neurodegenerative diseases |
|---|
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and the polyglutamine diseases are believed to be caused by protein misfolding and aggregation that eventually lead to neuronal dysfunctions, which are suggested to be reversible and hence ideal therapeutic targets. However, the precise mechanisms involved in the protein misfolding-induced neuronal dysfunctions have remained poorly understood. In this study, aiming to elucidate the molecular mechanisms of reversible neuronal dysfunctions in neurodegenerative diseases in vivo, 1) we will analyze synaptic dysfunctions in Drosophila disease models by genetic modifier screening. 2) We will also evaluate time-dependent alterations in synaptic morphology and function in mouse models of neurodegenerative diseases by two-photon laser scanning microscopy.
Yoshida Group
| Project Title | Investigation of functional role of IL1RAPL1 in synapse formation and pathogenesis of mental retardation and autism |
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Mental retardation (MR) and autism are the most frequent cause of serious handicap in children and young adults. IL-1 receptor accessory protein-like 1 (IL1RAPL1) was initially identified as the product of an X-linked gene responsible for a nonsyndromic form of MR and subsequently, shown to be associated with autism. We recently demonstrated that IL1RAPL1 functions as a synaptogenic organizer inducing excitatory presynaptic differentiation through the extracellular domain and stimulating spinogenesis through the cytoplasmic domain. In fact, IL1RAPL1 knockout mice exhibited decreased synapse number in some brain regions. In this project, we will try to identify the components of the trans-synaptic synapse-organizing complex mediated by IL1RAPL1 using proteomic analysis and try to clarify the pathogenesis of MR and autism associated with mutations in the IL1RAPL1 gene.
Kinoshita Group
| Project Title | Proving neuropsychiatric pathology that involves disorganization of the septin cytoskeleton underpinning synaptic and glial membranes |
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Septins (SEPT1-14) are a family of polymerizing GTPases underlying presynaptic and glial membranes. Previous studies from other groups showed that dominant mutations of SEPT9 cause hereditary neuralgic amyotrophy and that septins are accumulated in postmortem brains of schizophrenia and bipolar disorder. We previously found that a brain-specific septin subunit SEPT4, a substrate for parkin, co-aggregates with alpha-synuclein in Parkinson disease and related neurodegenerative disorders. In this study we test whether septin disruption in dopaminergic neurons affect dopamine metabolism and cause synuclein pathology. We also assess the impact of septin disruption on glial function and pathology. Through our unique approach we hope to find novel biomarkers and therapeutic targets.
Collaborators
Tomita Group
| Project Title | Molecular mechanism of synaptic modulation of secretase activities |
|---|
Deposition of amyloid-beta peptide is implicated in the pathogenesis of Alzheimer disease. Several lines of evidence suggest that enzymatic activity of secretases, which are responsible enzymes for Abeta production, is modulated by synaptic activity. Secretases are also involved in the proteolytic processing of synaptic adhesion molecules that play an important role in synaptic function. However, the molecular relationships between secretase activity and synaptic function still remain unclear. In this project, we will analyze the molecular mechanism as well as the functional significance of synaptic modulation of secretase activities.
Takumi Group
| Project Title | Synaptic pathology of a mouse model of 15q duplication syndrome |
|---|
Autism is a complex psychiatric illness which has received considerable attention as a developmental brain disorder. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice using chromosome engineering to generate a 6.3-Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display autistic behavioral features. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. In this study we perform morphological analyses at the spine level to understand the molecular pathophysiology of abnormal social behavior.
Uchiyama Group
| Project Title | Protein degradation in axonal compartments and its impairment |
|---|
Different from neuronal somata and dendrites, the degradation system in axonal compartments remains largely unknown. The most important role of the axon is to transfer stimulus to the targets. It has been shown that impairment of autophagy in the axon may explain possible mechanism for axonopathy associated with neurodegeneration. However, molecular mechanism for autophagosome formation in the axonal compartments is largely unknown. To further understand protein degradation through autophagy in axonal compartments we produced transgenic mice expressing Atg9A, DFCP1, and Tom20 that are fused with fluorescence proteins, respectively. Using these mice that express Atg9A, an essential member of autophagosome formation, DFCP1 that relates to the initiation of autophagosome formation, or Tom 20, a receptor for proteins with mitochondrial targeting signal, we try to analyze precise molecular mechanism for autophagosome formation in axonal compartments and its impairment.
