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The Journal of Cell Biology Jul 2021In a neural circuit, synapses transfer information rapidly between neurons and transform this information during transfer. The diverse computational properties of... (Review)
Review
In a neural circuit, synapses transfer information rapidly between neurons and transform this information during transfer. The diverse computational properties of synapses are shaped by the interactions between pre- and postsynaptic neurons. How synapses are assembled to form a neural circuit, and how the specificity of synaptic connections is achieved, is largely unknown. Here, I posit that synaptic adhesion molecules (SAMs) organize synapse formation. Diverse SAMs collaborate to achieve the astounding specificity and plasticity of synapses, with each SAM contributing different facets. In orchestrating synapse assembly, SAMs likely act as signal transduction devices. Although many candidate SAMs are known, only a few SAMs appear to have a major impact on synapse formation. Thus, a limited set of collaborating SAMs likely suffices to account for synapse formation. Strikingly, several SAMs are genetically linked to neuropsychiatric disorders, suggesting that impairments in synapse assembly are instrumental in the pathogenesis of neuropsychiatric disorders.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Mental Disorders; Neurogenesis; Neurons; Signal Transduction; Synapses
PubMed: 34086051
DOI: 10.1083/jcb.202103052 -
The Journal of Physiology Mar 2017Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently... (Review)
Review
Astrocytes comprise half of the cells in the brain. Although astrocytes have traditionally been described as playing a supportive role for neurons, they have recently been recognized as active participants in the development and plasticity of dendritic spines and synapses. Astrocytes can eliminate dendritic spines, induce synapse formation, and regulate neurotransmission and plasticity. Dendritic spine and synapse impairments are features of many neurological disorders, including autism spectrum disorder, schizophrenia, and Alzheimer's disease. In this review we will present evidence from multiple neurological disorders demonstrating that changes in astrocyte-synapse interaction contribute to the pathologies. Genomic analysis has connected altered astrocytic gene expression with synaptic deficits in a number of neurological disorders. Alterations in astrocyte-secreted factors have been implicated in the neuronal morphology and synaptic changes seen in neurodevelopmental disorders, while alteration in astrocytic glutamate uptake is a core feature of multiple neurodegenerative disorders. This evidence clearly demonstrates that maintaining astrocyte-synapse interaction is crucial for normal central nervous system functioning. Obtaining a better understanding of the role of astrocytes at synapses in health and disease will provide a new avenue for future therapeutic targeting.
Topics: Animals; Astrocytes; Dendritic Spines; Humans; Nervous System Diseases; Neurodevelopmental Disorders; Synapses
PubMed: 27381164
DOI: 10.1113/JP270988 -
Pflugers Archiv : European Journal of... Jan 2021The variety of taste sensations, including sweet, umami, bitter, sour, and salty, arises from diverse taste cells, each of which expresses specific taste sensor... (Review)
Review
The variety of taste sensations, including sweet, umami, bitter, sour, and salty, arises from diverse taste cells, each of which expresses specific taste sensor molecules and associated components for downstream signal transduction cascades. Recent years have witnessed major advances in our understanding of the molecular mechanisms underlying transduction of basic tastes in taste buds, including the identification of the bona fide sour sensor H channel OTOP1, and elucidation of transduction of the amiloride-sensitive component of salty taste (the taste of sodium) and the TAS1R-independent component of sweet taste (the taste of sugar). Studies have also discovered an unconventional chemical synapse termed "channel synapse" which employs an action potential-activated CALHM1/3 ion channel instead of exocytosis of synaptic vesicles as the conduit for neurotransmitter release that links taste cells to afferent neurons. New images of the channel synapse and determinations of the structures of CALHM channels have provided structural and functional insights into this unique synapse. In this review, we discuss the current view of taste transduction and neurotransmission with emphasis on recent advances in the field.
Topics: Animals; Humans; Synapses; Synaptic Transmission; Taste; Taste Buds
PubMed: 32936320
DOI: 10.1007/s00424-020-02464-4 -
Journal of Neurophysiology Apr 2019The precise patterns of neuronal assembly during development determine all functional outputs of a nervous system; these may range from simple reflexes to learning,... (Review)
Review
The precise patterns of neuronal assembly during development determine all functional outputs of a nervous system; these may range from simple reflexes to learning, memory, cognition, etc. To understand how brain functions and how best to repair it after injury, disease, or trauma, it is imperative that we first seek to define fundamental steps mediating this neuronal assembly. To acquire the sophisticated ensemble of highly specialized networks seen in a mature brain, all proliferated and migrated neurons must extend their axonal and dendritic processes toward targets, which are often located at some distance. Upon contact with potential partners, neurons must undergo dramatic structural changes to become either a pre- or a postsynaptic neuron. This connectivity is cemented through specialized structures termed synapses. Both structurally and functionally, the newly formed synapses are, however, not static as they undergo consistent changes in order for an animal to meet its behavioral needs in a changing environment. These changes may be either in the form of new synapses or an enhancement of their synaptic efficacy, referred to as synaptic plasticity. Thus, synapse formation is not restricted to neurodevelopment; it is a process that remains active throughout life. As the brain ages, either the lack of neuronal activity or cell death render synapses dysfunctional, thus giving rise to neurodegenerative disorders. This review seeks to highlight salient steps that are involved in a neuron's journey, starting with the establishment, maturation, and consolidation of synapses; we particularly focus on identifying key players involved in the synaptogenic program. We hope that this endeavor will not only help the beginners in this field to understand how brain networks are assembled in the first place but also shed light on various neurodevelopmental, neurological, neurodegenerative, and neuropsychiatric disorders that involve synaptic inactivity or dysfunction.
Topics: Animals; Humans; Neurodegenerative Diseases; Neurodevelopmental Disorders; Neurogenesis; Neuronal Plasticity; Synapses
PubMed: 30759043
DOI: 10.1152/jn.00833.2018 -
Cell Reports Jan 2018Aging brains undergo cognitive decline, associated with decreased neuronal synapse number and function and altered metabolism. Astrocytes regulate neuronal synapse...
Aging brains undergo cognitive decline, associated with decreased neuronal synapse number and function and altered metabolism. Astrocytes regulate neuronal synapse formation and function in development and adulthood, but whether these properties change during aging, contributing to neuronal dysfunction, is unknown. We addressed this by generating aged and adult astrocyte transcriptomes from multiple mouse brain regions. These data provide a comprehensive RNA-seq database of adult and aged astrocyte gene expression, available online as a resource. We identify astrocyte genes altered by aging across brain regions and regionally unique aging changes. Aging astrocytes show minimal alteration of homeostatic and neurotransmission-regulating genes. However, aging astrocytes upregulate genes that eliminate synapses and partially resemble reactive astrocytes. We further identified heterogeneous expression of synapse-regulating genes between astrocytes from different cortical regions. We find that alterations to astrocytes in aging create an environment permissive to synapse elimination and neuronal damage, potentially contributing to aging-associated cognitive decline.
Topics: Aging; Animals; Astrocytes; Cerebral Cortex; Databases, Nucleic Acid; Mice; Mice, Transgenic; Synapses; Synaptic Transmission; Transcriptome; Up-Regulation
PubMed: 29298427
DOI: 10.1016/j.celrep.2017.12.039 -
Nature Reviews. Neuroscience Mar 2021The function of neuronal circuits relies on the properties of individual neuronal cells and their synapses. We propose that a substantial degree of synapse formation and... (Review)
Review
The function of neuronal circuits relies on the properties of individual neuronal cells and their synapses. We propose that a substantial degree of synapse formation and function is instructed by molecular codes resulting from transcriptional programmes. Recent studies on the Neurexin protein family and its ligands provide fundamental insight into how synapses are assembled and remodelled, how synaptic properties are specified and how single gene mutations associated with neurodevelopmental and psychiatric disorders might modify the operation of neuronal circuits and behaviour. In this Review, we first summarize insights into Neurexin function obtained from various model organisms. We then discuss the mechanisms and logic of the cell type-specific regulation of Neurexin isoforms, in particular at the level of alternative mRNA splicing. Finally, we propose a conceptual framework for how combinations of synaptic protein isoforms act as 'senders' and 'readers' to instruct synapse formation and the acquisition of cell type-specific and synapse-specific functional properties.
Topics: Alternative Splicing; Animals; Humans; Nerve Tissue Proteins; Receptors, Cell Surface; Synapses
PubMed: 33420412
DOI: 10.1038/s41583-020-00415-7 -
Journal of Integrative Neuroscience Jun 2022The cellular, molecular and physiological basis of cognition has proved elusive until emerging studies on astrocytes. The appearance of a deliberate aggregating element... (Review)
Review
The cellular, molecular and physiological basis of cognition has proved elusive until emerging studies on astrocytes. The appearance of a deliberate aggregating element in cellular neurophysiology was difficult to satisfy computationally with excitatory and inhibitory neuron physiology alone. Similarly, the complex behavioral outputs of cognition are challenging to test experimentally. Astrocytic reception and control of synaptic communication has provided the possibility for study of the missing element. The advancement of genetic and neurophysiological techniques have now demonstrated astrocytes respond to neural input and subsequently provide the ability for neural synchronization and assembly at multiple and single synaptic levels. Considering the most recent evidence, it is becoming clear that astrocytes contribute to cognition. Is it possible then that our cognitive experience is essentially the domain of astrocyte physiology, ruminating on neural input, and controlling neural output? Although the molecular and cellular complexities of cognition in the human nervous system cannot be overstated, in order to gain a better understanding of the current evidence, an astrocyte centric basis of cognition will be considered from a philosophical, biological and computational perspective.
Topics: Astrocytes; Cognition; Humans; Neurons; Synapses
PubMed: 35864764
DOI: 10.31083/j.jin2104112 -
Cell Reports Nov 2017The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an...
The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an experimentally accessible model synapse routinely studied in animal models to explore fundamental aspects of synaptic form and function. Here, we combined morphological techniques, super-resolution imaging, and proteomic profiling to reveal the detailed cellular and molecular architecture of the human NMJ. Human NMJs were significantly smaller, less complex, and more fragmented than mouse NMJs. In contrast to mice, human NMJs were also remarkably stable across the entire adult lifespan, showing no signs of age-related degeneration or remodeling. Super-resolution imaging and proteomic profiling revealed distinctive distribution of active zone proteins and differential expression of core synaptic proteins and molecular pathways at the human NMJ. Taken together, these findings reveal human-specific cellular and molecular features of the NMJ that distinguish them from comparable synapses in other mammalian species.
Topics: Aging; Animals; Humans; Motor Neurons; Muscle, Skeletal; Nervous System; Neuromuscular Junction; Proteomics; Synapses; Synaptic Transmission
PubMed: 29186674
DOI: 10.1016/j.celrep.2017.11.008 -
Cells Nov 2019The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several... (Review)
Review
The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.
Topics: Agrin; Animals; Humans; Models, Animal; Neurogenesis; Neuromuscular Junction; Neurons; Synapses
PubMed: 31744142
DOI: 10.3390/cells8111448 -
Current Biology : CB Nov 2014Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and...
Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Südhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site.
Topics: Biological Transport; Models, Biological; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 25458214
DOI: 10.1016/j.cub.2014.10.024