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Molecular and Cellular Neurosciences Sep 2023The pre- and post-synaptic compartments contain a variety of molecules that are known to recycle between the plasma membrane and intracellular organelles. The recycling... (Review)
Review
The pre- and post-synaptic compartments contain a variety of molecules that are known to recycle between the plasma membrane and intracellular organelles. The recycling steps have been amply described in functional terms, with, for example, synaptic vesicle recycling being essential for neurotransmitter release, and postsynaptic receptor recycling being a fundamental feature of synaptic plasticity. However, synaptic protein recycling may also serve a more prosaic role, simply ensuring the repeated use of specific components, thereby minimizing the energy expenditure on the synthesis of synaptic proteins. This type of process has been recently described for components of the extracellular matrix, which undergo long-loop recycling (LLR), to and from the cell body. Here we suggest that the energy-saving recycling of synaptic components may be more widespread than is generally acknowledged, potentially playing a role in both synaptic vesicle protein usage and postsynaptic receptor metabolism.
Topics: Synaptic Vesicles; Neurons; Synaptic Transmission; Cell Membrane; Neuronal Plasticity
PubMed: 37236414
DOI: 10.1016/j.mcn.2023.103862 -
Proceedings of the National Academy of... Oct 2021Recent work has highlighted roles for thermodynamic phase behavior in diverse cellular processes. Proteins and nucleic acids can phase separate into three-dimensional...
Recent work has highlighted roles for thermodynamic phase behavior in diverse cellular processes. Proteins and nucleic acids can phase separate into three-dimensional liquid droplets in the cytoplasm and nucleus and the plasma membrane of animal cells appears tuned close to a two-dimensional liquid-liquid critical point. In some examples, cytoplasmic proteins aggregate at plasma membrane domains, forming structures such as the postsynaptic density and diverse signaling clusters. Here we examine the physics of these surface densities, employing minimal simulations of polymers prone to phase separation coupled to an Ising membrane surface in conjunction with a complementary Landau theory. We argue that these surface densities are a phase reminiscent of prewetting, in which a molecularly thin three-dimensional liquid forms on a usually solid surface. However, in surface densities the solid surface is replaced by a membrane with an independent propensity to phase separate. We show that proximity to criticality in the membrane dramatically increases the parameter regime in which a prewetting-like transition occurs, leading to a broad region where coexisting surface phases can form even when a bulk phase is unstable. Our simulations naturally exhibit three-surface phase coexistence even though both the membrane and the polymer bulk only display two-phase coexistence on their own. We argue that the physics of these surface densities may be shared with diverse functional structures seen in eukaryotic cells.
Topics: Animals; Cell Membrane; Cytoplasm; Polymers; Post-Synaptic Density; Proteins; Thermodynamics
PubMed: 34599097
DOI: 10.1073/pnas.2103401118 -
PloS One 2018Densin is a scaffold protein known to associate with key elements of neuronal signaling. The present study examines the distribution of densin at the ultrastructural...
Densin is a scaffold protein known to associate with key elements of neuronal signaling. The present study examines the distribution of densin at the ultrastructural level in order to reveal potential sites that can support specific interactions of densin. Immunogold electron microscopy on hippocampal cultures shows intense labeling for densin at postsynaptic densities (PSDs), but also some labeling at extrasynaptic plasma membranes of soma and dendrites and endoplasmic reticulum. At the PSD, the median distance of label from the postsynaptic membrane was ~27 nm, with the majority of label (90%) confined within 40 nm from the postsynaptic membrane, indicating predominant localization of densin at the PSD core. Depolarization (90 mM K+ for 2 min) promoted a slight shift of densin label within the PSD complex resulting in 77% of label remaining within 40 nm from the postsynaptic membrane. Densin molecules firmly embedded within the PSD may target a minor pool of CaMKII to substrates at the PSD core.
Topics: Animals; Brain; Brain Mapping; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Membrane; Cells, Cultured; Dendrites; Endoplasmic Reticulum; Female; Hippocampus; Immunohistochemistry; Male; Nerve Tissue Proteins; Neurons; Post-Synaptic Density; Protein Binding; Rats; Rats, Sprague-Dawley; Sialoglycoproteins; Subcellular Fractions
PubMed: 30325965
DOI: 10.1371/journal.pone.0205859 -
Nature Communications Oct 2023Alzheimer's disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer's disease has been associated with the...
Alzheimer's disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer's disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Post-Synaptic Density; Alzheimer Disease; N-Methylaspartate; Membrane Proteins; Disks Large Homolog 4 Protein; Receptors, N-Methyl-D-Aspartate
PubMed: 37891164
DOI: 10.1038/s41467-023-42295-2 -
Neural Regeneration Research Mar 2018Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These... (Review)
Review
Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.
PubMed: 29623913
DOI: 10.4103/1673-5374.228710 -
Cell Reports Nov 2023Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter...
Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.
Topics: Receptors, GABA-A; Synapses; Carrier Proteins; Receptors, Neurotransmitter; gamma-Aminobutyric Acid
PubMed: 37910506
DOI: 10.1016/j.celrep.2023.113331 -
Journal of Molecular Biology Jan 2023Signal transduction at the synapse is mediated by a variety of protein-lipid interactions, which are vital for the spatial and temporal regulation of synaptic vesicle... (Review)
Review
Signal transduction at the synapse is mediated by a variety of protein-lipid interactions, which are vital for the spatial and temporal regulation of synaptic vesicle biogenesis, neurotransmitter release, and postsynaptic receptor activation. Therefore, our understanding of synaptic transmission cannot be completed until the elucidation of these critical protein-lipid interactions. On this front, recent advances in nanodiscs have vastly expanded our ability to probe and reprogram membrane biology in synapses. Here, we summarize the progress of the nanodisc toolbox and discuss future directions in this exciting field.
Topics: Synapses; Synaptic Transmission; Synaptic Vesicles; Lipid Metabolism; Nanostructures; Membrane Proteins
PubMed: 35872069
DOI: 10.1016/j.jmb.2022.167757 -
Molecular and Cellular Neurosciences Jun 2020Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique... (Review)
Review
Neuronal dendrites are highly branched and specialized compartments with distinct structures and secretory organelles (e.g., spines, Golgi outposts), and a unique cytoskeletal organization that includes microtubules of mixed polarity. Dendritic membranes are enriched with proteins, which specialize in the formation and function of the post-synaptic membrane of the neuronal synapse. How these proteins partition preferentially in dendrites, and how they traffic in a manner that is spatiotemporally accurate and regulated by synaptic activity are long-standing questions of neuronal cell biology. Recent studies have shed new insights into the spatial control of dendritic membrane traffic, revealing new classes of proteins (e.g., septins) and cytoskeleton-based mechanisms with dendrite-specific functions. Here, we review these advances by revisiting the fundamental mechanisms that control membrane traffic at the levels of protein sorting and motor-driven transport on microtubules and actin filaments. Overall, dendrites possess unique mechanisms for the spatial control of membrane traffic, which might have specialized and co-evolved with their highly arborized morphology.
Topics: Animals; Cytoskeleton; Dendrites; Golgi Apparatus; Humans; Microtubules; Neurons; Protein Transport
PubMed: 32294508
DOI: 10.1016/j.mcn.2020.103492 -
Cells Oct 2022The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic...
The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic synapses, it is established that the presence of astrocytic processes and their structural arrangements varies considerably between and within brain regions and between synapses of the same neuron. In contrast, less is known about the organization of astrocytic processes at GABAergic synapses although bi-directional signaling is known to exist at these synapses too. Therefore, we established super-resolution expansion microscopy of GABAergic synapses and nearby astrocytic processes in the of the mouse hippocampal CA1 region. By visualizing the presynaptic vesicular GABA transporter and the postsynaptic clustering protein gephyrin, we documented the subsynaptic heterogeneity of GABAergic synaptic contacts. We then compared the volume distribution of astrocytic processes near GABAergic synapses between individual synapses and with glutamatergic synapses. We made two novel observations. First, astrocytic processes were more abundant at the GABAergic synapses with large postsynaptic gephyrin clusters. Second, astrocytic processes were less abundant in the vicinity of GABAergic synapses compared to glutamatergic, suggesting that the latter may be selectively approached by astrocytes. Because of the GABA transporter distribution, we also speculate that this specific arrangement enables more efficient re-uptake of GABA into presynaptic terminals.
Topics: Animals; GABA Plasma Membrane Transport Proteins; Mice; Presynaptic Terminals; Receptors, GABA-A; Synapses; gamma-Aminobutyric Acid
PubMed: 36231112
DOI: 10.3390/cells11193150 -
Frontiers in Cellular Neuroscience 2015To achieve proper synaptic development and function, coordinated signals must pass between the pre- and postsynaptic membranes. Such transsynaptic signals can be... (Review)
Review
To achieve proper synaptic development and function, coordinated signals must pass between the pre- and postsynaptic membranes. Such transsynaptic signals can be comprised of receptors and secreted ligands, membrane associated receptors, and also pairs of synaptic cell adhesion molecules. A critical open question bridging neuroscience, developmental biology, and cell biology involves identifying those signals and elucidating how they function. Recent work in Drosophila and vertebrate systems has implicated a family of proteins, the Teneurins, as a new transsynaptic signal in both the peripheral and central nervous systems. The Teneurins have established roles in neuronal wiring, but studies now show their involvement in regulating synaptic connections between neurons and bridging the synaptic membrane and the cytoskeleton. This review will examine the Teneurins as synaptic cell adhesion molecules, explore how they regulate synaptic organization, and consider how some consequences of human Teneurin mutations may have synaptopathic origins.
PubMed: 26074772
DOI: 10.3389/fncel.2015.00204