シンポジウム
15 脳の若返りによる生涯可塑性誘導-iPlasticity-臨界期機構の解明を操作
15 Inducing lifelong plasticity (iPlasticity) by brain rejuvenation: elucidation and manipulation of critical period mechanisms
座長：高橋 琢哉（横浜市立大学大学院医学研究科）・宮田 麻理子（東京女子医科大学医学部生理学講座神経生理学分野） |
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| 2022年7月1日 16:10～16:34 沖縄コンベンションセンター 会議場B1 第3会場
2S03e-01
小脳における発達期シナプス刈り込みの活動依存的制御
Activity-dependent regulation of developmental synapse pruning in the cerebellum
*狩野 方伸(1,2)
1. 東京大学大学院医学系研究科、2. 東京大学ニューロインテリジェンス国際研究機構
*Masanobu Kano(1,2)
1. Grad Sch Med, Univ of Tokyo, Tokyo, Japan, 2. WPI-IRCN, Univ of Tokyo, Tokyo, Japan
Keyword: synapse pruning, cerebellum, Purkinje cell, climbing fiber
Functional neural circuits of mature animals are shaped during postnatal development by eliminating early-formed redundant synapses and strengthening of necessary connections. Postnatal development of excitatory synapses onto Purkinje cells (PCs) in the cerebellum has been a representative model of synapse remodeling in the developing brain. PCs are sole output neurons from the cerebellar cortex and receive two distinct glutamatergic excitatory inputs from climbing fibers (CFs) and parallel fibers (PFs). During postnatal development, these two types of synapses are formed and refined through distinct processes, but significantly influence each other to establish mature synaptic wiring patterns of PCs. In neonatal rodents, PCs are innervated by more than five CFs with similar synaptic strengths. During the first three postnatal weeks, single CFs are selectively strengthened while redundant CFs are pruned, and most PCs become innervated by single strong CFs. These processes consist of four distinct phases: (1) selective strengthening of inputs from a single CF among multiple CFs innervating the soma of each PC from around postnatal day 3 (~P3) to ~ P7, (2) translocation and expansion of innervation territory of the strongest CF (‘winner’ CF) to PC dendrites from ~P9, (3) pruning of somatic synapses of the ‘winner’ CF and those of weaker CFs (‘loser’ CFs) from ~P7 to ~P11, (4) pruning of the remaining somatic CF synapses from ~P12 to ~P17. It is known that CF synapse elimination is dependent on neural activity. We have shown that the P/Q-type voltage-dependent calcium channel (P/Q-VDCC) in PCs is required for all of the four phases, whereas the type 1 metabotropic glutamate receptor (mGlu1) is rather specifically involved in the late phase of CF elimination. In this talk, I will make an overview of molecular, cellular and neural circuit mechanisms underlying CF synapse remodeling. Then I will discuss how neural activity regulates the distinct phases of CF synapse elimination through P/Q-VDCC and transcription factors in PCs. | | 2022年7月1日 16:34～16:58 沖縄コンベンションセンター 会議場B1 第3会場
2S03e-02
マウス視覚野における階層的ネットワークは並列モジュールとして発達する
A modular strategy for the development of hierarchical networks in mouse visual system
*大木 研一(1)
1. 東京大学
*Kenichi Ohki(1)
1. The University of Tokyo
Keyword: visual system, mouse, connectivity, development
The hierarchical and parallel network is a fundamental structure of the mammalian brain. During development, lower- and higher-order thalamic nuclei and many cortical areas in the visual system form interareal connections and build hierarchical dorsal and ventral streams. The classic hypothesis for development of visual network wiring involves the bottom-up theory wherein neural connections are sequentially formed alongside a hierarchical structure from the lower to higher areas. However, this sequential strategy is inefficient for building the entire visual network comprising numerous interareal connections. We show that neural pathways from the mouse retina to V1 or dorsal/ventral higher visual areas (HVAs) via lower- or higher-order thalamic nuclei form as three parallel modules before cortico-cortical connections, inconsistent with the sequential strategy. A few days postnatally, these parallel modules convey retina-derived activity and retinotopic information. Subsequently, before eye-opening, cortical connections among V1 and HVAs emerge to combine these modules. The retina-derived activity propagating initial modules is necessary to establish retinotopic inter-module connections. Thus, the visual network develops in a modular manner—initial establishment of parallel modules from the retina to cortical areas and their subsequent concatenation. This study suggests that brain has an efficient strategy for the development of a hierarchical network comprising numerous areas. | | 2022年7月1日 16:58～17:22 沖縄コンベンションセンター 会議場B1 第3会場
2S03e-03
発達過程における生き残るシナプスと刈り込まれるシナプスのプレシナプス神経伝達物質放出能の違い
Distinct transmitter release kinetics from surviving and eliminating presynaptic terminals
*宮田 麻理子(1)
1. 東京女子医科大学
*Mariko Miyata(1)
1. Tokyo Women's Medical Univ.
Keyword: thalamus, sensory dependent plasticity, synapse elimination, presynapse
Maturation of the neural circuits involves initial formation of the excessive number of synapses, followed by selective strengthening of surviving synapses and elimination of redundant connections. The selective synapse strengthening and elimination occur in the experience-dependent manner in many brain regions and are considered fundamental steps for neuronal network maturation. Thus, extensive studies have been performed to understand the detailed molecular mechanisms. However, it is still unknown how transmitter release mechanism, a crucial function for synaptic transmission, develops differently between eventually strengthened “winner” presynaptic terminals and destined to eliminated “loser” presynaptic terminals before the circuit maturation. Also, it is unclear how experience-dependent synaptic activity affects the presynaptic functional establishments.
In this studies, we focused onto a synapse in a rodent whisker-sensory fiber to the sensory thalamus (VPM). In mouse, whisker-mediated sensory information is transmitted from the V2 region of the principal trigeminal nucleus (PrV2) in the brainstem to VPM by whisker-sensory afferent fibers. The innervation of the sensory fibers to a VPM neuron developmentally changes from multiple fibers- innervation to single fiber- innervation. This synapse elimination is interrupted by whisker deprivation when the mice start the active whisking postnatal 12 day.
Here, we found distinct developments of transmitter release kinetics at surviving and eliminating presynaptic terminals using direct patch-clamp recording from each whsker sensory fiber terminal. At surviving terminals, the total number of releasable vesicles enlarges first, and capacity for rapid exocytosis is established experience-dependently thereafter. At eliminating terminals, not only transmitter release mechanism, but also calcium current and terminal size exhibit no developmental maturation. By contrast, developmental changes of action potential waveforms are indistinguishable between surviving or eliminating terminals and showed no experience-independence. Thus, we reveal pathway-specific, experience-dependent, and experience-independent developmental presynaptic maturation, leading to a deeper understanding of brain neuronal circuit establishment. | | 2022年7月1日 17:22～17:46 沖縄コンベンションセンター 会議場B1 第3会場
2S03e-04
Oscillatory signature of critical period plasticity
*Takao Hensch(1,2)
1. Harvard / IRCN (UTokyo), 2. Boston Children’s Hospital
Keyword: Gamma rhythm, Parvalbumin, Fast-spiking, Visual cortex
Critical periods are developmental windows of rapid plasticity and remodeling of brain networks, whose trajectories are not yet fully understood. Here, we identify transient γ-oscillations induced by sensory imbalance as a robust signature of rapid thalamocortical (TC) plasticity. Monocular deprivation acutely induced a transient (<3 hr) peak in EEG γ-power (~40Hz) specifically within mouse binocular visual (V1) cortex, but only when the critical period was open (juvenile C57Bl/6J mice or adults after dark-rearing; Lynx1-deficient or diazepam-rescued GAD65 knock-out mice). Conversely, gene-targeted disinhibition of parvalbumin (PV+) networks enhanced γ power broadly and extended critical period plasticity into adulthood. Rapid TC input loss onto fast-spiking (PV+) inhibitory interneurons (but not nearby pyramidal cells) was further observed within hours of deprivation in a critical period TC slice preserving the visual pathway. Computational modeling explained the origin of these brief cortical interneuronal γ-rhythms (ING) and their role in rewiring TC networks at critical period onset. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after deprivation. Taken together, our findings reveal the first synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe and potentially correct derailed developmental trajectories or recover from brain injury in adulthood. | | 2022年7月1日 17:46～18:10 沖縄コンベンションセンター 会議場B1 第3会場
2S03e-05
ヒト生体脳におけるシナプス可塑性の可視化と操作
Visualization and pharmacoligical manipulation of synapticplasticity in living human brain
*高橋 琢哉(1)
1. 横浜市立大学大学院医学研究科
*Takuya Takahashi(1)
1. Yokohama City University Graduate School of Medicine
Keyword: Synapse, plasticity, AMPA receptor, PET
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. Since the cloning of AMPARs approximately two decades ago, enormous number of papers have reported the importance of AMPARs on neuronal functions including diseases. 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. Although rodent neuronal disease models are elegant and well characterized, it remains unclear if these animal models fully mimic human disease. 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. We detected elevated [11C]K-2 signals in the temporal lobe of the hemisphere with epileptic foci where the 99mECD-SPECT blood flow signal was lower compared to the contralateral hemisphere. Further, we detected significant positive correlation between [11C]K-2-signals and protein amount of AMPARs with surgically removed tissue from epileptic patients. Thus, our PET probe for AMPARs specifically detects AMPARs and the first PET probe to visualize AMPAR in living human brain. We are currently imaging patients with 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. | | | |
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