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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 -
Neuropsychopharmacology : Official... Jan 2015In this review we examine the current understanding of how genetic deficits associated with neurodevelopmental disorders may impact synapse assembly. We then go on to... (Review)
Review
In this review we examine the current understanding of how genetic deficits associated with neurodevelopmental disorders may impact synapse assembly. We then go on to discuss how the critical periods for these genetic deficits will shape the nature of future clinical interventions.
Topics: Child; Developmental Disabilities; Humans; Nerve Tissue Proteins; Neurogenesis; Neuronal Plasticity; Synapses
PubMed: 24990427
DOI: 10.1038/npp.2014.163 -
Frontiers in Immunology 2022Interactions among immune cells are essential for the development of adaptive immune responses. The immunological synapse (IS) provides a specialized platform for... (Review)
Review
Interactions among immune cells are essential for the development of adaptive immune responses. The immunological synapse (IS) provides a specialized platform for integration of signals and intercellular communication between T lymphocytes and antigen presenting cells (APCs). In the T cell the reorganization of surface molecules at the synaptic interface is initiated by T cell receptor binding to a cognate peptide-major histocompatibility complex on the APC surface and is accompanied by a polarized remodelling of the cytoskeleton and centrosome reorientation to a subsynaptic position. Although there is a general agreement on polarizing signals and mechanisms driving centrosome reorientation during IS assembly, the primary events that prepare for centrosome repositioning remain largely unexplored. It has been recently shown that in resting lymphocytes a local polymerization of filamentous actin (F-actin) at the centrosome contributes to anchoring this organelle to the nucleus. During early stages of IS formation centrosomal F-actin undergoes depletion, allowing for centrosome detachment from the nucleus and its polarization towards the synaptic membrane. We recently demonstrated that in CD4 T cells the reduction in centrosomal F-actin relies on the activity of a centrosome-associated proteasome and implicated the ciliopathy-related Bardet-Biedl syndrome 1 protein in the dynein-dependent recruitment of the proteasome 19S regulatory subunit to the centrosome. In this short review we will feature our recent findings that collectively provide a new function for BBS proteins and the proteasome in actin dynamics, centrosome polarization and T cell activation.
Topics: Actins; Lymphocyte Activation; Lymphocytes; Proteasome Endopeptidase Complex; Synapses
PubMed: 35222415
DOI: 10.3389/fimmu.2022.830835 -
Experimental & Molecular Medicine Apr 2018
Topics: Animals; Brain Diseases; Humans; Neurogenesis; Neurons; Synapses; Synaptic Transmission
PubMed: 29628499
DOI: 10.1038/s12276-018-0049-6 -
Advances in Protein Chemistry and... 2019The presynaptic active zone, composed of evolutionarily conserved protein complexes, is a specialized area that serves to orchestrate precise and efficient... (Review)
Review
The presynaptic active zone, composed of evolutionarily conserved protein complexes, is a specialized area that serves to orchestrate precise and efficient neurotransmitter release by organizing various presynaptic proteins involved in mediating docking and priming of synaptic vesicles, recruiting voltage-gated calcium channels, and modulating presynaptic nerve terminals with aligned postsynaptic structures. Among membrane proteins localized to active zone, presynaptic neurexins and LAR-RPTPs (leukocyte common antigen-related receptor tyrosine phosphatase) have emerged as hubs that orchestrate both shared and distinct extracellular synaptic adhesion pathways. In this chapter, we discuss intracellular signaling cascades involved in recruiting various intracellular proteins at both excitatory and inhibitory synaptic sites. In particular, we highlight recent studies on key active zone proteins that physically and functionally link these cascades with neurexins and LAR-RPTPs in both vertebrate and invertebrate model systems. These studies allow us to build a general, universal view of how presynaptic active zones operate together with postsynaptic structures in neural circuits.
Topics: Animals; Humans; Membrane Proteins; Nerve Tissue Proteins; Neurons; Synapses; Synaptic Transmission
PubMed: 31036296
DOI: 10.1016/bs.apcsb.2018.11.008 -
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 Feb 2022Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh)...
Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-enriched astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses; conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep-layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.
Topics: Astrocytes; Hedgehog Proteins; Neurogenesis; Neurons; Synapses
PubMed: 35196485
DOI: 10.1016/j.celrep.2022.110416 -
Neuron Jan 2021Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As... (Review)
Review
Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As the biosynthetic machinery is largely restricted to the somatodendritic domain, the vast majority of presynaptic components are synthesized in the neuronal soma, packaged into synaptic precursor vesicles, and actively transported along the axon to sites of presynaptic biogenesis. In contrast with the significant progress that has been made in understanding synaptic transmission and processing of information at the post-synapse, comparably little is known about the formation and dynamic remodeling of the presynaptic compartment. We review here our current understanding of the mechanisms that govern the biogenesis, transport, and assembly of the key components for presynaptic neurotransmission, discuss how alterations in presynaptic assembly may impact nervous system function or lead to disease, and outline key open questions for future research.
Topics: Animals; Humans; Neurogenesis; Presynaptic Terminals; Protein Transport; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 33098763
DOI: 10.1016/j.neuron.2020.09.038 -
Neuron Oct 2003The mechanisms that govern synapse formation and elimination are fundamental to our understanding of neural development and plasticity. The wiring of neural circuitry... (Review)
Review
The mechanisms that govern synapse formation and elimination are fundamental to our understanding of neural development and plasticity. The wiring of neural circuitry requires that vast numbers of synapses be formed in a relatively short time. The subsequent refinement of neural circuitry involves the formation of additional synapses coincident with the disassembly of previously functional synapses. There is increasing evidence that activity-dependent plasticity also involves the formation and disassembly of synapses. While we are gaining insight into the mechanisms of both synapse assembly and disassembly, we understand very little about how these phenomena are related to each other and how they might be coordinately controlled to achieve the precise patterns of synaptic connectivity in the nervous system. Here, we review our current understanding of both synapse assembly and disassembly in an effort to unravel the relationship between these fundamental developmental processes.
Topics: Animals; Brain; Humans; Neuromuscular Junction; Neuronal Plasticity; Synapses
PubMed: 14556707
DOI: 10.1016/s0896-6273(03)00608-1 -
The Journal of Cell Biology Feb 2022The physiological mechanisms driving synapse formation are elusive. Although numerous signals are known to regulate synapses, it remains unclear which signaling...
The physiological mechanisms driving synapse formation are elusive. Although numerous signals are known to regulate synapses, it remains unclear which signaling mechanisms organize initial synapse assembly. Here, we describe new tools, referred to as "SynTAMs" for synaptic targeting molecules, that enable localized perturbations of cAMP signaling in developing postsynaptic specializations. We show that locally restricted suppression of postsynaptic cAMP levels or of cAMP-dependent protein-kinase activity severely impairs excitatory synapse formation without affecting neuronal maturation, dendritic arborization, or inhibitory synapse formation. In vivo, suppression of postsynaptic cAMP signaling in CA1 neurons prevented formation of both Schaffer-collateral and entorhinal-CA1/temporoammonic-path synapses, suggesting a general principle. Retrograde trans-synaptic rabies virus tracing revealed that postsynaptic cAMP signaling is required for continuous replacement of synapses throughout life. Given that postsynaptic latrophilin adhesion-GPCRs drive synapse formation and produce cAMP, we suggest that spatially restricted postsynaptic cAMP signals organize assembly of postsynaptic specializations during synapse formation.
Topics: Animals; Cyclic AMP; Genetic Engineering; Hippocampus; Mice, Inbred C57BL; Signal Transduction; Single-Domain Antibodies; Synapses; Mice
PubMed: 34913963
DOI: 10.1083/jcb.202109111