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Article ; Online: Neuronal Plasticity and Age-Related Functional Decline in the Motor Cortex.

Inoue, Ritsuko / Nishimune, Hiroshi

2023 Volume 12, Issue 17

Abstract: Physiological aging causes a decline of motor function due to impairment of motor cortex function, losses of motor neurons and neuromuscular junctions, sarcopenia, and frailty. There is increasing evidence suggesting that the changes in motor function ... ...

Abstract	Physiological aging causes a decline of motor function due to impairment of motor cortex function, losses of motor neurons and neuromuscular junctions, sarcopenia, and frailty. There is increasing evidence suggesting that the changes in motor function start earlier in the middle-aged stage. The mechanism underlining the middle-aged decline in motor function seems to relate to the central nervous system rather than the peripheral neuromuscular system. The motor cortex is one of the responsible central nervous systems for coordinating and learning motor functions. The neuronal circuits in the motor cortex show plasticity in response to motor learning, including LTP. This motor cortex plasticity seems important for the intervention method mechanisms that revert the age-related decline of motor function. This review will focus on recent findings on the role of plasticity in the motor cortex for motor function and age-related changes. The review will also introduce our recent identification of an age-related decline of neuronal activity in the primary motor cortex of middle-aged
MeSH term(s)	Animals ; Mice ; Aging ; Brain ; Motor Cortex ; Neuronal Plasticity
Language	English
Publishing date	2023-08-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12172142
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Article ; Online: Similarity and Diversity of Presynaptic Molecules at Neuromuscular Junctions and Central Synapses.

Takikawa, Kenji / Nishimune, Hiroshi

Biomolecules

2022 Volume 12, Issue 2

Abstract: Synaptic transmission is essential for controlling motor functions and maintaining brain functions such as walking, breathing, cognition, learning, and memory. Neurotransmitter release is regulated by presynaptic molecules assembled in active zones of ... ...

Abstract	Synaptic transmission is essential for controlling motor functions and maintaining brain functions such as walking, breathing, cognition, learning, and memory. Neurotransmitter release is regulated by presynaptic molecules assembled in active zones of presynaptic terminals. The size of presynaptic terminals varies, but the size of a single active zone and the types of presynaptic molecules are highly conserved among neuromuscular junctions (NMJs) and central synapses. Three parameters play an important role in the determination of neurotransmitter release properties at NMJs and central excitatory/inhibitory synapses: the number of presynaptic molecular clusters, the protein families of the presynaptic molecules, and the distance between presynaptic molecules and voltage-gated calcium channels. In addition, dysfunction of presynaptic molecules causes clinical symptoms such as motor and cognitive decline in patients with various neurological disorders and during aging. This review focuses on the molecular mechanisms responsible for the functional similarities and differences between excitatory and inhibitory synapses in the peripheral and central nervous systems, and summarizes recent findings regarding presynaptic molecules assembled in the active zone. Furthermore, we discuss the relationship between functional alterations of presynaptic molecules and dysfunction of NMJs or central synapses in diseases and during aging.
MeSH term(s)	Aging/metabolism ; Humans ; Neuromuscular Junction/metabolism ; Presynaptic Terminals/metabolism ; Synapses/metabolism ; Synaptic Transmission
Language	English
Publishing date	2022-01-21
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12020179
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Article ; Online: Coenzyme Q

Inoue, Ritsuko / Miura, Masami / Yanai, Shuichi / Nishimune, Hiroshi

Scientific reports

2023 Volume 13, Issue 1, Page(s) 4323

Abstract: Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15-18 months old show motor function decline, which can be restored to the young adult level by ... ...

Abstract	Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15-18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q
MeSH term(s)	Humans ; Middle Aged ; Young Adult ; Mice ; Animals ; Infant ; Ubiquinone/pharmacology ; Ubiquinone/metabolism ; Motor Cortex/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Dietary Supplements
Chemical Substances	Ubiquinone (1339-63-5)
Language	English
Publishing date	2023-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-31510-1
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Article: Impairment Mechanisms and Intervention Approaches for Aged Human Neuromuscular Junctions.

Badawi, Yomna / Nishimune, Hiroshi

Frontiers in molecular neuroscience

2020 Volume 13, Page(s) 568426

Abstract: The neuromuscular junction (NMJ) is a chemical synapse formed between a presynaptic motor neuron and a postsynaptic muscle cell. NMJs in most vertebrate species share many essential features; however, some differences distinguish human NMJs from others. ... ...

Abstract	The neuromuscular junction (NMJ) is a chemical synapse formed between a presynaptic motor neuron and a postsynaptic muscle cell. NMJs in most vertebrate species share many essential features; however, some differences distinguish human NMJs from others. This review will describe the pre- and postsynaptic structures of human NMJs and compare them to NMJs of laboratory animals. We will focus on age-dependent declines in function and changes in the structure of human NMJs. Furthermore, we will describe insights into the aging process revealed from mouse models of accelerated aging. In addition, we will compare aging phenotypes to other human pathologies that cause impairments of pre- and postsynaptic structures at NMJs. Finally, we will discuss potential intervention approaches for attenuating age-related NMJ dysfunction and sarcopenia in humans.
Language	English
Publishing date	2020-11-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2020.568426
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Article ; Online: Super-resolution microscopy for analyzing neuromuscular junctions and synapses.

Badawi, Yomna / Nishimune, Hiroshi

Neuroscience letters

2019 Volume 715, Page(s) 134644

Abstract: Super-resolution microscopy techniques offer subdiffraction limited resolution that is two- to ten-fold improved compared to that offered by conventional confocal microscopy. This breakthrough in resolution for light microscopy has contributed to new ... ...

Abstract	Super-resolution microscopy techniques offer subdiffraction limited resolution that is two- to ten-fold improved compared to that offered by conventional confocal microscopy. This breakthrough in resolution for light microscopy has contributed to new findings in neuroscience and synapse biology. This review will focus on the Structured Illumination Microscopy (SIM), Stimulated emission depletion (STED) microscopy, and Stochastic optical reconstruction microscopy (STORM) / Single molecule localization microscopy (SMLM) techniques and compare them for the better understanding of their differences and their suitability for the analysis of synapse biology. In addition, we will discuss a few practical aspects of these microscopic techniques, including resolution, image acquisition speed, multicolor capability, and other advantages and disadvantages. Tips for the improvement of microscopy will be introduced; for example, information resources for recommended dyes, the limitations of multicolor analysis, and capabilities for live imaging. In addition, we will summarize how super-resolution microscopy has been used for analyses of neuromuscular junctions and synapses.
MeSH term(s)	Animals ; Humans ; Microscopy, Fluorescence/methods ; Neuromuscular Junction/cytology ; Synapses
Language	English
Publishing date	2019-11-22
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2019.134644
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Article ; Online: Active zones of mammalian neuromuscular junctions: formation, density, and aging.

Nishimune, Hiroshi

Annals of the New York Academy of Sciences

2012 Volume 1274, Page(s) 24–32

Abstract: Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization use presynaptic voltage-dependent ... ...

Abstract	Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization use presynaptic voltage-dependent calcium channels (VDCCs) in NMJs as scaffolding proteins. VDCCs interact extracellularly with the muscle-derived synapse organizer, laminin β2 and interact intracellularly with active zone-specific proteins, such as Bassoon, CAST/Erc2/ELKS2alpha, ELKS, Piccolo, and RIMs. These molecular mechanisms are supported by studies in P/Q- and N-type VDCCs double-knockout mice, and they are consistent with the pathological conditions of Lambert-Eaton myasthenic syndrome and Pierson syndrome, which are caused by autoantibodies against VDCCs or by a laminin β2 mutation. During normal postnatal maturation, NMJs maintain the density of active zones, while NMJs triple their size. However, active zones become impaired during aging. Propitiously, muscle exercise ameliorates the active zone impairment in aged NMJs, which suggests the potential for therapeutic strategies.
MeSH term(s)	Abnormalities, Multiple/immunology ; Abnormalities, Multiple/metabolism ; Aging/metabolism ; Animals ; Autoantibodies/immunology ; Calcium Channels/immunology ; Calcium Channels/metabolism ; Eye Abnormalities/immunology ; Eye Abnormalities/metabolism ; Humans ; Lambert-Eaton Myasthenic Syndrome/immunology ; Lambert-Eaton Myasthenic Syndrome/metabolism ; Myasthenic Syndromes, Congenital ; Nephrotic Syndrome/immunology ; Nephrotic Syndrome/metabolism ; Nerve Tissue Proteins/metabolism ; Neuromuscular Junction/metabolism ; Presynaptic Terminals/metabolism ; Pupil Disorders/immunology ; Pupil Disorders/metabolism
Chemical Substances	Autoantibodies ; Calcium Channels ; Nerve Tissue Proteins
Language	English
Publishing date	2012-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	211003-9
ISSN	1749-6632 ; 0077-8923
ISSN (online)	1749-6632
ISSN	0077-8923
DOI	10.1111/j.1749-6632.2012.06836.x
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Article ; Online: Practical Anatomy of the Neuromuscular Junction in Health and Disease.

Nishimune, Hiroshi / Shigemoto, Kazuhiro

Neurologic clinics

2018 Volume 36, Issue 2, Page(s) 231–240

Abstract: Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs. One muscle fiber has one NMJ, which is innervated by one motor nerve terminal. NMJs are ...

Abstract	Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs. One muscle fiber has one NMJ, which is innervated by one motor nerve terminal. NMJs are excitatory synapses that use P/Q-type voltage-gated calcium channels to release the neurotransmitter acetylcholine. Acetylcholine receptors accumulate at the postsynaptic specialization called the end plate on the muscle fiber membrane, the sarcolemma. Proteins essential for the organization of end plates include agrin secreted from nerve terminals, Lrp4 and MuSK receptors for agrin, and Dok-7 and rapsyn cytosolic proteins in the muscle.
MeSH term(s)	Animals ; Humans ; Neuromuscular Junction/anatomy & histology ; Neuromuscular Junction/pathology
Language	English
Publishing date	2018-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1013148-6
ISSN	1557-9875 ; 0733-8619
ISSN (online)	1557-9875
ISSN	0733-8619
DOI	10.1016/j.ncl.2018.01.009
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Article ; Online: Molecular mechanism of active zone organization at vertebrate neuromuscular junctions.

Nishimune, Hiroshi

Molecular neurobiology

2011 Volume 45, Issue 1, Page(s) 1–16

Abstract: Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the ... ...

Abstract	Organization of presynaptic active zones is essential for development, plasticity, and pathology of the nervous system. Recent studies indicate a trans-synaptic molecular mechanism that organizes the active zones by connecting the pre- and the postsynaptic specialization. The presynaptic component of this trans-synaptic mechanism is comprised of cytosolic active zone proteins bound to the cytosolic domains of voltage-dependent calcium channels (P/Q-, N-, and L-type) on the presynaptic membrane. The postsynaptic component of this mechanism is the synapse organizer (laminin β2) that is expressed by the postsynaptic cell and accumulates specifically on top of the postsynaptic specialization. The pre- and the postsynaptic components interact directly between the extracellular domains of calcium channels and laminin β2 to anchor the presynaptic protein complex in front of the postsynaptic specialization. Hence, the presynaptic calcium channel functions as a scaffolding protein for active zone organization and as an ion-conducting channel for synaptic transmission. In contrast to the requirement of calcium influx for synaptic transmission, the formation of the active zone does not require the calcium influx through the calcium channels. Importantly, the active zones of adult synapses are not stable structures and require maintenance for their integrity. Furthermore, aging or diseases of the central and peripheral nervous system impair the active zones. This review will focus on the molecular mechanisms that organize the presynaptic active zones and summarize recent findings at the neuromuscular junctions and other synapses.
MeSH term(s)	Animals ; Calcium Channels/chemistry ; Calcium Channels/metabolism ; Calcium Channels/physiology ; Humans ; Neuromuscular Junction/chemistry ; Neuromuscular Junction/metabolism ; Neuromuscular Junction/physiology ; Post-Synaptic Density/chemistry ; Post-Synaptic Density/metabolism ; Post-Synaptic Density/physiology ; Presynaptic Terminals/chemistry ; Presynaptic Terminals/metabolism ; Presynaptic Terminals/physiology ; Synaptic Membranes/chemistry ; Synaptic Membranes/metabolism ; Synaptic Membranes/physiology ; Synaptic Transmission/physiology ; Vertebrates/metabolism ; Vertebrates/physiology
Chemical Substances	Calcium Channels
Language	English
Publishing date	2011-12-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-011-8216-y
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Article ; Online: Transsynaptic channelosomes: non-conducting roles of ion channels in synapse formation.

Nishimune, Hiroshi

Channels (Austin, Tex.)

2011 Volume 5, Issue 5, Page(s) 432–439

Abstract: Recent findings demonstrate that synaptic channels are directly involved in the formation and maintenance of synapses by interacting with synapse organizers. The synaptic channels on the pre- and postsynaptic membranes possess non-conducting roles in ... ...

Abstract	Recent findings demonstrate that synaptic channels are directly involved in the formation and maintenance of synapses by interacting with synapse organizers. The synaptic channels on the pre- and postsynaptic membranes possess non-conducting roles in addition to their functional roles as ion-conducting channels required for synaptic transmission. For example, presynaptic voltage-dependent calcium channels link the target-derived synapse organizer laminin β2 to cytomatrix of the active zone and function as scaffolding proteins to organize the presynaptic active zones. Furthermore, postsynaptic δ2-type glutamate receptors organize the synapses by forming transsynaptic protein complexes with presynaptic neurexins through synapse organizer cerebellin 1 precursor proteins. Interestingly, the synaptic clustering of AMPA receptors is regulated by neuronal activity-regulated pentraxins, while postsynaptic differentiation is induced by the interaction of postsynaptic calcium channels and thrombospondins. This review will focus on the non-conducting functions of ion-channels that contribute to the synapse formation in concert with synapse organizers and active-zone-specific proteins.
MeSH term(s)	Animals ; Calcium Channels/metabolism ; Humans ; Laminin/metabolism ; Nerve Tissue Proteins/metabolism ; Presynaptic Terminals/metabolism ; Protein Precursors/metabolism ; Receptors, AMPA/metabolism ; Synaptic Membranes/metabolism ; Synaptic Transmission/physiology ; Thrombospondins/metabolism
Chemical Substances	CBLN1 protein, human ; Calcium Channels ; Laminin ; Nerve Tissue Proteins ; Protein Precursors ; Receptors, AMPA ; Thrombospondins ; laminin beta2 (124148-86-3)
Language	English
Publishing date	2011-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2262854-X
ISSN	1933-6969 ; 1933-6969
ISSN (online)	1933-6969
ISSN	1933-6969
DOI	10.4161/chan.5.5.16472
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Article ; Online: The role of laminins in the organization and function of neuromuscular junctions.

Rogers, Robert S / Nishimune, Hiroshi

Matrix biology : journal of the International Society for Matrix Biology

2017 Volume 57-58, Page(s) 86–105

Abstract: The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of ...

Abstract	The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.
Language	English
Publishing date	2017-01
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2016.08.008
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