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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 -
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 -
The EMBO Journal Aug 2020Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an...
Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.
Topics: Animals; Coculture Techniques; Complement C1q; Complement C3; Hippocampus; Membrane Glycoproteins; Mice; Mice, Knockout; Microglia; Neurons; Phosphatidylserines; Receptors, Immunologic; Synapses
PubMed: 32657463
DOI: 10.15252/embj.2020105380 -
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 -
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 -
ELife Mar 2021Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood....
Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.
Topics: Animals; HEK293 Cells; Hippocampus; Humans; Mice; Mice, Knockout; Mutation; Receptors, G-Protein-Coupled; Receptors, Peptide; Synapses
PubMed: 33646123
DOI: 10.7554/eLife.65717 -
Cell Aug 2018Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and...
Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing formation and modulation of compartmentalized synaptic assemblies is unclear. Here, we used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (PSD) scaffold proteins led to formation of PSD-like assemblies via phase separation. The reconstituted PSD-like assemblies can cluster receptors, selectively concentrate enzymes, promote actin bundle formation, and expel inhibitory postsynaptic proteins. Additionally, the condensed phase PSD assemblies have features that are distinct from those in homogeneous solutions and fit for synaptic functions. Thus, we have built a molecular platform for understanding how neuronal synapses are formed and dynamically regulated.
Topics: Animals; Brain; Disks Large Homolog 4 Protein; Hippocampus; Light; Mice; Microscopy, Confocal; Neurogenesis; Neuronal Plasticity; Neurons; Post-Synaptic Density; Scattering, Radiation; Signal Transduction; Synapses; Synaptic Transmission
PubMed: 30078712
DOI: 10.1016/j.cell.2018.06.047 -
Experimental & Molecular Medicine Apr 2018
Topics: Animals; Brain Diseases; Humans; Neurogenesis; Neurons; Synapses; Synaptic Transmission
PubMed: 29628499
DOI: 10.1038/s12276-018-0049-6 -
Nature Feb 2024The assembly and specification of synapses in the brain is incompletely understood. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion...
The assembly and specification of synapses in the brain is incompletely understood. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion G-protein-coupled receptor-mediates synapse formation in the hippocampus but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of Gα signalling and recruitment of phase-separated postsynaptic protein scaffolds. We found that cell-type-specific alternative splicing of Lphn3 controls the LPHN3 G-protein-coupling mode, resulting in LPHN3 variants that predominantly signal through Gα or Gα. CRISPR-mediated manipulation of Lphn3 alternative splicing that shifts LPHN3 from a Gα- to a Gα-coupled mode impaired synaptic connectivity as severely as the overall deletion of Lphn3, suggesting that Gα signalling by LPHN3 splice variants mediates synapse formation. Notably, Gα-coupled, but not Gα-coupled, splice variants of LPHN3 also recruit phase-transitioned postsynaptic protein scaffold condensates, such that these condensates are clustered by binding of presynaptic teneurin and FLRT ligands to LPHN3. Moreover, neuronal activity promotes alternative splicing of the synaptogenic Gα-coupled variant of LPHN3. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways: Gα signalling and clustered phase separation of postsynaptic protein scaffolds.
Topics: Animals; Mice; Alternative Splicing; GTP-Binding Protein alpha Subunits, G12-G13; GTP-Binding Protein alpha Subunits, Gs; Ligands; Receptors, G-Protein-Coupled; Receptors, Peptide; Synapses; Signal Transduction
PubMed: 38233523
DOI: 10.1038/s41586-023-06913-9 -
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