神経化学
理事会企画シンポジウム
シナプス研究によってヒトの精神神経病理は説明できるのか？ |
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| 7月6日（木） 14:20-16:20 Room A
1SY④-1
神経疾患への細胞・分子・シナプスアプローチ
Cellular-molecular-synaptic approach to neuronal disease
高橋 智幸
沖縄科学技術大学院大学
Tomoyuki Takahashi
OIST
"In Parkinson’s (PD) or Alzheimer’s (AD) disease, alpha-synuclein or tau propagates to particular brain regions and impairs their functions. In our slice and culture models, alpha-synuclein or tau loaded or seeded in presynaptic terminals impaired vesicle endocytosis and attenuated EPSCs evoked at high-frequencies. Endocytic dysfunction reduces recycling vesicles, thereby impairing high frequency synaptic transmission, which is indispensable for dopamine release and LTP induction. Both alpha-synuclein and tau assemble microtubules (MTs) in presynaptic terminals in slice and culture. The monomeric GTPase dynamin is a key molecule involved in vesicle endocytic fission and a MT-binding protein. Over-assembled MTs by pathogenic proteins capture cytosolic dynamins, thereby impairing endocytosis. Consistently, in culture, dynamin 1 overexpression rescued endocytosis impaired by seeded tau. In both slice and culture, the MT-depolymerizers rescued endocytosis impaired by alpha-synuclein or tau and rescued EPSCs from rundown. Among 22 peptides we synthesized, one corresponding to 560-571 of pleckstrin-homolog of dynamin 1 (PHDP5) significantly inhibited the MT-dynamin 1 binding and rescued endocytosis and synaptic transmission impaired by tau in presynaptic terminals. Thus, our synaptic approach can potentially provide us therapeutic tools against neuronal diseases. " | | 7月6日（木） 14:20-16:20 Room A
1SY④-2
なぜシナプス強度分布を考える必要があるのか？：統合失調症病態生理の再考
Neurocomputation is biased by heavily-weighted synapses in mental disorders
林 朗子
理研・CBS・多階層精神疾患研究チーム
Akiko Hayashi-Takagi
RKEN Center for Brain Science
Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the multi-scale effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra large (XL) synapses, which evoked supralinear synaptic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were significantly more abundant in the postmortem brains of schizophrenia patients than in those of matched controls. The currently dominant hypothesis of schizophrenia pathophysiology is a reduction in spine density (the over-pruning hypothesis). However, our results presented here suggest that the hypothesis may need to be revised. Given the distorted dendritic and somatic integration via extra-large spines, more in-depth investigations into the interactions between intra-spine and dendritic computations and their effect on brain (dys)function are needed. | | 7月6日（木） 14:20-16:20 Room A
1SY④-3
Translational medicine of synapse physiology
高橋 琢哉
横浜市立大学 大学院医学研究科 生理学
Takuya Takahashi
Dept. of Physiol., Grad. Sch. of Med., Yokohama City Univ., Yokohama, Japan
"Glutamatergic synapses play central roles in almost all of neuronal functions such as learning, motor and sensory functions. Among glutamate receptors, AMPARs are the “actual mediator” at glutamatergic synapses. Despite the accumulation of knowledge of physiological roles of AMPARs, its clinical translation is limited. Main reason for this is that we are not currently able to visualize AMPARs in living human brain. Characterization of these diseases with AMPARs in living human brain should provide us biological basis of neuropsychiatric disorders. We developed novel PET probe for AMPARs, named [11C]K-2. We detected [11C]K-2 signals reflecting specific binding to AMPARs in rat, non-human primate and human. Using this tracer, we characterized synaptic features of neuropsychiatric disorders.Further, we have recently identified CRMP2-binding compound, edonerpic maleate, facilitates synaptic AMPAR delivery and results in the acceleration of motor function recovery after brain damage in rodent and non-human primate.These small compounds will be promising tools to translate the knowledge of synaptic physiology to the elucidation of human neuropsychiatric disorders and brand-new clinical settings." | | 7月6日（木） 14:20-16:20 Room A
1SY④-4
統合失調症の精神病理と病態生理を結合させる
Connecting the psychopathology and pathophysiology of schizophrenia
高橋 英彦
東京医科歯科大学 精神行動医科学
Hidehiko Takahashi
Department of Psychiatry and Behavioral Sciences, Department of Psychiatry and Behavioral Sciences, Tokyo, Japan
Bleuler‘s concept of a loosening of associations, ie, abnormalities in semantic relations between ideas, was offered as a fundamental psychopathology of schizophrenia. Wernicke proposed a sejunction hypothesis, which posits a disruption of anatomical brain connectivity as the cause of psychosis. These provide complementary perspectives on a failure of functional integration in the brain. To establish a link between the symptoms of schizophrenia and the underlying molecular and neuronal pathophysiology, the dysconnection hypothesis has been proposed (Friston et al 2016).The dysconnection hypothesis and predictive coding explains how the physiological consequences of abnormal synaptic connectivity causes computational impairments in the brain and how this lead to false inference.Using in vivo human brain imaging and AI techniques, we have recently elucidated pathophysiology of loosening of associations, which has not been achieved for over 100 years. Next, we are trying to obtain mechanistic understanding of hallucination, another fundamental psychopathology of schizophrenia on the basis of the dysconnection hypothesis and predictive coding. | |
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