-
IEEE Transactions on Nanobioscience Apr 2023In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This...
In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This randomness of synaptic MC contributes to the randomness of the electrochemical downstream signal in the postsynaptic cell, called postsynaptic membrane potential (PSP). Since the randomness of the PSP is relevant for neural computation and learning, characterizing the statistics of the PSP is critical. However, the statistical characterization of the synaptic reaction-diffusion process is difficult because the reversible bi-molecular reaction of NTs with receptors renders the system nonlinear. Consequently, there is currently no model available which characterizes the impact of the statistics of postsynaptic receptor activation on the PSP. In this work, we propose a novel statistical model for the synaptic reaction-diffusion process in terms of the chemical master equation (CME). We further propose a novel numerical method which allows to compute the CME efficiently and we use this method to characterize the statistics of the PSP. Finally, we present results from stochastic particle-based computer simulations which validate the proposed models. We show that the biophysical parameters governing synaptic transmission shape the autocovariance of the receptor activation and, ultimately, the statistics of the PSP. Our results suggest that the processing of the synaptic signal by the postsynaptic cell effectively mitigates synaptic noise while the statistical characteristics of the synaptic signal are preserved. The results presented in this paper contribute to a better understanding of the impact of the randomness of synaptic signal transmission on neuronal information processing.
Topics: Synaptic Transmission; Neurons; Computer Simulation; Models, Statistical; Neurotransmitter Agents; Synapses; Models, Neurological
PubMed: 35709120
DOI: 10.1109/TNB.2022.3183692 -
International Journal of General... 2023Synaptic plasticity is the capacity of synaptic transmission between neurons to be strengthened or weakened. There are many signal molecules accumulated in the... (Review)
Review
Synaptic plasticity is the capacity of synaptic transmission between neurons to be strengthened or weakened. There are many signal molecules accumulated in the presynaptic and postsynaptic membranes that can lead to the regulation of synaptic plasticity and involvement in numerous of neurological and psychiatric diseases, including anxiety disorder. However, the regulatory mechanisms of synaptic plasticity in the development of anxiety disorder have not been well summarized. This review mainly aims to discuss the biological functions and mechanisms of synaptic plasticity-related molecules in anxiety disorder, with a particular focus on the metabotropic glutamate receptors, brain-derived neurotrophic factor, hyperpolarization-activated cyclic nucleotide-gated channels, and postsynaptic density 95. The summarized functions and mechanisms of synaptic plasticity-related molecules in anxiety will provide insight into novel neuroplasticity modifications for targeted therapy for anxiety.
PubMed: 37435365
DOI: 10.2147/IJGM.S413176 -
Nature Communications Feb 2022The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to...
The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Cells, Cultured; Dendritic Spines; Hippocampus; Long-Term Synaptic Depression; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neuronal Plasticity; Neurons; Proteome; Proteomics; Pyramidal Cells; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Potentials; Mice
PubMed: 35115539
DOI: 10.1038/s41467-022-28301-z -
Advances in Biological Regulation Jan 2020Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate... (Review)
Review
Diacylglycerol kinases (DGKs) contribute to an important part of intracellular signaling because, in addition to reducing diacylglycerol levels, they generate phosphatidic acid (PtdOH) Recent research has led to the discovery of ten mammalian DGK isoforms, all of which are found in the mammalian brain. Many of these isoforms have studied functions within the brain, while others lack such understanding in regards to neuronal roles, regulation, and structural dynamics. However, while previously a neuronal function for DGKθ was unknown, it was recently found that DGKθ is required for the regulation of synaptic vesicle endocytosis and work is currently being conducted to elucidate the mechanism behind this regulation. Here we will review some of the roles of all mammalian DGKs and hypothesize additional roles. We will address the topic of redundancy among the ten DGK isoforms and discuss the possibility that DGKθ, among other DGKs, may have unstudied postsynaptic functions. We also hypothesize that in addition to DGKθ's presynaptic endocytic role, DGKθ might also regulate the endocytosis of AMPA receptors and other postsynaptic membrane proteins.
Topics: Animals; Diacylglycerol Kinase; Endocytosis; Humans; Isoenzymes; Mice; Neurons; Phosphatidic Acids; Receptors, AMPA; Synaptic Membranes; Synaptic Vesicles
PubMed: 31836314
DOI: 10.1016/j.jbior.2019.100688 -
Proceedings of the National Academy of... May 2022Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex→dentate gyrus (EC→DG) synapses, but the molecular...
Five decades ago, long-term potentiation (LTP) of synaptic transmission was discovered at entorhinal cortex→dentate gyrus (EC→DG) synapses, but the molecular determinants of EC→DG LTP remain largely unknown. Here, we show that the presynaptic neurexin–ligand cerebellin-4 (Cbln4) is highly expressed in the entorhinal cortex and essential for LTP at EC→DG synapses, but dispensable for basal synaptic transmission at these synapses. Cbln4, when bound to cell-surface neurexins, forms transcellular complexes by interacting with postsynaptic DCC (deleted in colorectal cancer) or neogenin-1. DCC and neogenin-1 act as netrin and repulsive guidance molecule-a (RGMa) receptors that mediate axon guidance in the developing brain, but their binding to Cbln4 raised the possibility that they might additionally function in the mature brain as postsynaptic receptors for presynaptic neurexin/Cbln4 complexes, and that as such receptors, DCC or neogenin-1 might mediate EC→DG LTP that depends on Cbln4. Indeed, we observed that neogenin-1, but not DCC, is abundantly expressed in dentate gyrus granule cells, and that postsynaptic neogenin-1 deletions in dentate granule cells blocked EC→DG LTP, but again did not affect basal synaptic transmission similar to the presynaptic Cbln4 deletions. Thus, binding of presynaptic Cbln4 to postsynaptic neogenin-1 renders EC→DG synapses competent for LTP, but is not required for establishing these synapses or for otherwise enabling their function.
Topics: Animals; Dentate Gyrus; Ligands; Long-Term Potentiation; Membrane Proteins; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Netrin Receptors; Protein Precursors; Synapses; Synaptic Transmission
PubMed: 35544694
DOI: 10.1073/pnas.2123421119 -
Frontiers in Molecular Neuroscience 2023Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the...
Postsynaptic neurotransmitter receptors and their associated scaffolding proteins assemble into discrete, nanometer-scale subsynaptic domains (SSDs) within the postsynaptic membrane at both excitatory and inhibitory synapses. Intriguingly, postsynaptic receptor SSDs are mirrored by closely apposed presynaptic active zones. These trans-synaptic molecular assemblies are thought to be important for efficient neurotransmission because they concentrate postsynaptic receptors near sites of presynaptic neurotransmitter release. While previous studies have characterized the role of synaptic activity in sculpting the number, size, and distribution of postsynaptic SSDs at established synapses, it remains unknown whether neurotransmitter signaling is required for their initial assembly during synapse development. Here, we evaluated synaptic nano-architecture under conditions where presynaptic neurotransmitter release was blocked prior to, and throughout synaptogenesis with tetanus neurotoxin (TeNT). In agreement with previous work, neurotransmitter release was not required for the formation of excitatory or inhibitory synapses. The overall size of the postsynaptic specialization at both excitatory and inhibitory synapses was reduced at chronically silenced synapses. However, both AMPARs and GABARs still coalesced into SSDs, along with their respective scaffold proteins. Presynaptic active zone assemblies, defined by RIM1, were smaller and more numerous at silenced synapses, but maintained alignment with postsynaptic AMPAR SSDs. Thus, basic features of synaptic nano-architecture, including assembly of receptors and scaffolds into trans-synaptically aligned structures, are intrinsic properties that can be further regulated by subsequent activity-dependent mechanisms.
PubMed: 37602191
DOI: 10.3389/fnmol.2023.1232795 -
Proceedings of the National Academy of... Feb 2020Synaptic communication requires the expression of functional postsynaptic receptors that match the presynaptically released neurotransmitter. The ability of neurons to...
Synaptic communication requires the expression of functional postsynaptic receptors that match the presynaptically released neurotransmitter. The ability of neurons to switch the transmitter they release is increasingly well documented, and these switches require changes in the postsynaptic receptor population. Although the activity-dependent molecular mechanism of neurotransmitter switching is increasingly well understood, the basis of specification of postsynaptic neurotransmitter receptors matching the newly expressed transmitter is unknown. Using a functional assay, we show that sustained application of glutamate to embryonic vertebrate skeletal muscle cells cultured before innervation is necessary and sufficient to up-regulate ionotropic glutamate receptors from a pool of different receptors expressed at low levels. Up-regulation of these ionotropic receptors is independent of signaling by metabotropic glutamate receptors. Both imaging of glutamate-induced calcium elevations and Western blots reveal ionotropic glutamate receptor expression prior to immunocytochemical detection. Sustained application of glutamate to skeletal myotomes in vivo is necessary and sufficient for up-regulation of membrane expression of the GluN1 NMDA receptor subunit. Pharmacological antagonists and morpholinos implicate p38 and Jun kinases and MEF2C in the signal cascade leading to ionotropic glutamate receptor expression. The results suggest a mechanism by which neuronal release of transmitter up-regulates postsynaptic expression of appropriate transmitter receptors following neurotransmitter switching and may contribute to the proper expression of receptors at the time of initial innervation.
Topics: Animals; Calcium; Female; Glutamic Acid; Mitogen-Activated Protein Kinase 8; Muscle Cells; Neurons; Neurotransmitter Agents; Receptors, N-Methyl-D-Aspartate; Synapses; Xenopus
PubMed: 32041885
DOI: 10.1073/pnas.1916600117 -
Advances in Neurobiology 2023The architecture of the presynaptic release site is exquisitely designed to facilitate and regulate synaptic vesicle exocytosis. With the identification of some of the...
The architecture of the presynaptic release site is exquisitely designed to facilitate and regulate synaptic vesicle exocytosis. With the identification of some of the building blocks of the active zone and the advent of super resolution imaging techniques, we are beginning to understand the morphological and functional properties of synapses in great detail. Presynaptic release sites consist of the plasma membrane, the cytomatrix, and dense projections. These three components are morphologically distinct but intimately connected with each other and with postsynaptic specializations, ensuring the fidelity of synaptic vesicle tethering, docking, and fusion, as well as signal detection. Although the morphology and molecular compositions of active zones may vary among species, tissues, and cells, global architectural design of the release sites is highly conserved.
Topics: Humans; Biological Transport; Exocytosis; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 37615861
DOI: 10.1007/978-3-031-34229-5_1 -
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 -
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