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Neuron Dec 2022The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous...
The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
Topics: Mice; Animals; Longevity; Synapses; Neurons; Brain; Disks Large Homolog 4 Protein
PubMed: 36202095
DOI: 10.1016/j.neuron.2022.09.009 -
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 -
Science (New York, N.Y.) Feb 2019Bidirectional signaling by cell adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. We found that the adhesion G...
Bidirectional signaling by cell adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. We found that the adhesion G protein-coupled receptors latrophilin-2 and latrophilin-3 selectively direct formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two transcellular ligands: fibronectin leucine-rich repeat transmembrane proteins (FLRTs) and teneurins. In transgenic mice in vivo, both binding activities were required for input-specific synapse formation, which suggests that coincident binding of both ligands is necessary for synapse formation. In cultured neurons in vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations.
Topics: Animals; CA1 Region, Hippocampal; HEK293 Cells; Humans; Membrane Glycoproteins; Membrane Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Protein Binding; Receptors, G-Protein-Coupled; Receptors, Peptide; Synapses
PubMed: 30792275
DOI: 10.1126/science.aav7969 -
Cell Nov 2023Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity...
Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.
Topics: Animals; Mice; Brain; Mice, Transgenic; Proteome; Proteomics; Synapses; Synaptosomes
PubMed: 37918396
DOI: 10.1016/j.cell.2023.09.028 -
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 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 -
Neuroscience Letters May 2021In neurons, microtubules (MTs) provide routes for transport throughout the cell and structural support for dendrites and axons. Both stable and dynamic MTs are necessary... (Review)
Review
In neurons, microtubules (MTs) provide routes for transport throughout the cell and structural support for dendrites and axons. Both stable and dynamic MTs are necessary for normal neuronal functions. Research in the last two decades has demonstrated that MTs play additional roles in synaptic structure and function in both pre- and postsynaptic elements. Here, we review current knowledge of the functions that MTs perform in excitatory and inhibitory synapses, as well as in the neuromuscular junction and other specialized synapses, and discuss the implications that this knowledge may have in neurological disease.
Topics: Animals; Dendritic Spines; Humans; Microtubules; Nervous System Diseases; Neuronal Plasticity; Synapses
PubMed: 33775740
DOI: 10.1016/j.neulet.2021.135850 -
Seminars in Cell & Developmental Biology May 2023Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size... (Review)
Review
Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size throughout life; these changes are thought to be associated with formation and reorganization of neuronal networks underlying learning and memory. As spines in the brain are surrounded by the microenvironment including neighboring cells and the extracellular matrix, their protrusion requires generation of force to push against these structures. In turn, neighboring cells receive force from protruding spines. Recent studies have identified BAR-domain proteins as being involved in membrane deformation to initiate spine formation. In addition, forces for dendritic filopodium extension and activity-induced spine expansion are generated through cooperation between actin polymerization and clutch coupling. On the other hand, force from expanding spines affects neurotransmitter release from presynaptic terminals. Here, we review recent advances in our understanding of the physical aspects of synapse formation and plasticity, mainly focusing on spine dynamics.
Topics: Dendritic Spines; Synaptic Transmission; Neurons; Synapses; Neuronal Plasticity
PubMed: 35659473
DOI: 10.1016/j.semcdb.2022.05.017 -
Frontiers in Neural Circuits 2020Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate... (Review)
Review
Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate they are highly coordinated entities. Imaging techniques, that enable physiology at the resolution of individual synapses to be investigated, have allowed the presynaptic activity level of the synapse to be related to postsynaptic function. This approach has revealed that neuronal activity induces the pre- and post-synapse to be functionally correlated and that subsets of synapses are more susceptible to certain forms of synaptic plasticity. As presynaptic function is often examined in isolation from postsynaptic properties, the effect it has on the post-synapse is not fully understood. However, since postsynaptic receptors at excitatory synapses respond to release of glutamate, it follows that they may be differentially regulated depending on the frequency of its release. Therefore, examining postsynaptic properties in the context of presynaptic function may be a useful way to approach a broad range of questions on synaptic physiology. In this review, we focus on how optophysiology tools have been utilized to study relationships between the pre- and the post-synapse. Multiple imaging techniques have revealed correlations in synaptic properties from the submicron to the dendritic level. Optical tools together with advanced imaging techniques are ideally suited to illuminate this area further, due to the spatial resolution and control they allow.
Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Humans; Neuronal Plasticity; Presynaptic Terminals; Receptors, AMPA; Synapses; Synaptic Potentials; Synaptic Transmission
PubMed: 32308573
DOI: 10.3389/fncir.2020.00009 -
Molecular and Cellular Neurosciences Mar 2023The postsynaptic density (PSD) of excitatory synapses is built from a wide variety of scaffolding proteins, receptors, and signaling molecules that collectively... (Review)
Review
The postsynaptic density (PSD) of excitatory synapses is built from a wide variety of scaffolding proteins, receptors, and signaling molecules that collectively orchestrate synaptic transmission. Seminal work over the past decades has led to the identification and functional characterization of many PSD components. In contrast, we know far less about how these constituents are assembled within synapses, and how this organization contributes to synapse function. Notably, recent evidence from high-resolution microscopy studies and in silico models, highlights the importance of the precise subsynaptic structure of the PSD for controlling the strength of synaptic transmission. Even further, activity-driven changes in the distribution of glutamate receptors are acknowledged to contribute to long-term changes in synaptic efficacy. Thus, defining the mechanisms that drive structural changes within the PSD are important for a molecular understanding of synaptic transmission and plasticity. Here, we review the current literature on how the PSD is organized to mediate basal synaptic transmission and how synaptic activity alters the nanoscale organization of synapses to sustain changes in synaptic strength.
Topics: Synapses; Synaptic Transmission; Receptors, Glutamate; Post-Synaptic Density; Nanostructures; Neuronal Plasticity
PubMed: 36720293
DOI: 10.1016/j.mcn.2023.103819