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PLoS Computational Biology Mar 2021Short-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic...
Short-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic dynamics observed in experiments, we have developed a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show that it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.
Topics: Action Potentials; Algorithms; Likelihood Functions; Linear Models; Models, Neurological; Nerve Net; Neuronal Plasticity; Nonlinear Dynamics; Reproducibility of Results; Stochastic Processes; Synapses; Synaptic Transmission
PubMed: 33720935
DOI: 10.1371/journal.pcbi.1008013 -
The Journal of Neuroscience : the... Mar 2022Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline....
Palmitoylation may be relevant to the processes of learning and memory, and even disorders, such as post-traumatic stress disorder and aging-related cognitive decline. However, underlying mechanisms of palmitoylation in these processes remain unclear. Herein, we used acyl-biotin exchange, coimmunoprecipitation and biotinylation assays, and behavioral and electrophysiological methods, to explore whether palmitoylation is required for hippocampal synaptic transmission and fear memory formation, and involved in functional modification of synaptic proteins, such as postsynapse density-95 (PSD-95) and glutamate receptors, and detected if depalmitoylation by specific enzymes has influence on glutamatergic synaptic plasticity. Our results showed that global palmitoylation level, palmitoylation of PSD-95 and glutamate receptors, postsynapse density localization of PSD-95, surface expression of AMPARs, and synaptic strength of cultured hippocampal neurons were all enhanced by TTX pretreatment, and these can be reversed by inhibition of palmitoylation with palmitoyl acyl transferases inhibitors, 2-bromopalmitate and N-(tert-butyl) hydroxylamine hydrochloride. Importantly, we also found that acyl-protein thioesterase 1 (APT1)-mediated depalmitoylation is involved in palmitoylation of PSD-95 and glutamatergic synaptic transmission. Knockdown of APT1, not protein palmitoyl thioesterase 1, with shRNA, or selective inhibition, significantly increased AMPAR-mediated synaptic strength, palmitoylation levels, and synaptic or surface expression of PSD-95 and AMPARs. Results from hippocampal tissues and fear-conditioned rats showed that palmitoylation is required for synaptic strengthening and fear memory formation. These results suggest that palmitoylation and APT1-mediated depalmitoylation have critical effects on the regulation of glutamatergic synaptic plasticity, and it may serve as a potential target for learning and memory-associated disorders. Fear-related anxiety disorders, including post-traumatic stress disorder, are prevalent psychiatric conditions, and fear memory is associated with hyperexcitability in the hippocampal CA1 region. Palmitoylation is involved in learning and memory, but mechanisms coupling palmitoylation with fear memory acquisition remain poorly understood. This study demonstrated that palmitoylation is essential for postsynapse density-95 clustering and hippocampal glutamatergic synaptic transmission, and APT1-mediated depalmitoylation plays critical roles in the regulation of synaptic plasticity. Our study revealed that molecular mechanism about downregulation of APT1 leads to enhancement of AMPAR-mediated synaptic transmission, and that palmitoylation cycling is implicated in fear conditioning-induced synaptic strengthening and fear memory formation.
Topics: Animals; Hippocampus; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Rats; Synapses; Synaptic Transmission
PubMed: 35165175
DOI: 10.1523/JNEUROSCI.1741-21.2022 -
Cell Reports Oct 2023We describe a retrograde synaptic signal at the C. elegans GABAergic neuromuscular junction. At this synapse, GABA release is controlled by two voltage-activated...
We describe a retrograde synaptic signal at the C. elegans GABAergic neuromuscular junction. At this synapse, GABA release is controlled by two voltage-activated calcium channels (UNC-2/CaV2 and EGL-19/CaV1), and muscle responses are mediated by a single GABA receptor (UNC-49/GABA). Mutations inactivating UNC-49 or those preventing UNC-49 synaptic clustering cause retrograde defects in GABAergic motor neurons, whereby UNC-2/CaV2 levels at active zones, UNC-2 current, and pre-synaptic GABA release are decreased. Inactivating post-synaptic GABA receptors has no effect on GABA neuron EGL-19/CaV1 levels nor on several other pre-synaptic markers. The effect of GABA receptors on pre-synaptic strength is not a consequence of decreased GABA transmission and is input selective. Finally, pre-synaptic UNC-2/CaV2 levels are increased when post-synaptic GABA receptors are increased but are unaffected by increased extra-synaptic receptors. Collectively, these results suggest that clustered post-synaptic GABA receptors adjust the strength of their inputs by recruiting CaV2 to contacting active zones.
Topics: Animals; Caenorhabditis elegans; gamma-Aminobutyric Acid; Receptors, GABA-A; Synapses; Synaptic Transmission
PubMed: 37742192
DOI: 10.1016/j.celrep.2023.113161 -
Neurobiology of Disease Oct 2019The biophysical mechanisms underlying epileptogenesis and the generation of seizures remain to be better understood. Among many factors triggering epileptogenesis are... (Review)
Review
The biophysical mechanisms underlying epileptogenesis and the generation of seizures remain to be better understood. Among many factors triggering epileptogenesis are traumatic brain injury breaking normal synaptic homeostasis and genetic mutations disrupting ionic concentration homeostasis. Impairments in these mechanisms, as seen in various brain diseases, may push the brain network to a pathological state characterized by increased susceptibility to unprovoked seizures. Here, we review recent computational studies exploring the roles of ionic concentration dynamics in the generation, maintenance, and termination of seizures. We further discuss how ionic and synaptic homeostatic mechanisms may give rise to conditions which prime brain networks to exhibit recurrent spontaneous seizures and epilepsy.
Topics: Animals; Brain; Epilepsy; Homeostasis; Humans; Ions; Seizures; Synaptic Transmission
PubMed: 31150792
DOI: 10.1016/j.nbd.2019.104485 -
The Journal of Neuroscience : the... Feb 2020SynGAP is a potent regulator of biochemical signaling in neurons and plays critical roles in neuronal function. It was first identified in 1998, and has since been... (Review)
Review
SynGAP is a potent regulator of biochemical signaling in neurons and plays critical roles in neuronal function. It was first identified in 1998, and has since been extensively characterized as a mediator of synaptic plasticity. Because of its involvement in synaptic plasticity, SynGAP has emerged as a critical protein for normal cognitive function. In recent years, mutations in the gene have been shown to cause intellectual disability in humans and have been linked to other neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia. While the structure and biochemical function of SynGAP have been well characterized, a unified understanding of the various roles of SynGAP at the synapse and its contributions to neuronal function remains to be achieved. In this review, we summarize and discuss the current understanding of the multifactorial role of SynGAP in regulating neuronal function gathered over the last two decades.
Topics: Animals; Brain; Cognition; Humans; Neuronal Plasticity; Neurons; Synapses; Synaptic Transmission; ras GTPase-Activating Proteins
PubMed: 32075947
DOI: 10.1523/JNEUROSCI.0420-19.2020 -
Frontiers in Neural Circuits 2021Nitric oxide (NO) is of fundamental importance in regulating immune, cardiovascular, reproductive, neuromuscular, and nervous system function. It is rapidly synthesized... (Review)
Review
Nitric oxide (NO) is of fundamental importance in regulating immune, cardiovascular, reproductive, neuromuscular, and nervous system function. It is rapidly synthesized and cannot be confined, it is highly reactive, so its lifetime is measured in seconds. These distinctive properties (contrasting with classical neurotransmitters and neuromodulators) give rise to the concept of NO as a "volume transmitter," where it is generated from an active source, diffuses to interact with proteins and receptors within a sphere of influence or volume, but limited in distance and time by its short half-life. In the auditory system, the neuronal NO-synthetizing enzyme, nNOS, is highly expressed and tightly coupled to postsynaptic calcium influx at excitatory synapses. This provides a powerful activity-dependent control of postsynaptic intrinsic excitability via cGMP generation, protein kinase G activation and modulation of voltage-gated conductances. NO may also regulate vesicle mobility via retrograde signaling. This Mini Review focuses on the auditory system, but highlights general mechanisms by which NO mediates neuronal intrinsic plasticity and synaptic transmission. The dependence of NO generation on synaptic and sound-evoked activity has important local modulatory actions and NO serves as a "volume transmitter" in the auditory brainstem. It also has potentially destructive consequences during intense activity or on spill-over from other NO sources during pathological conditions, when aberrant signaling may interfere with the precisely timed and tonotopically organized auditory system.
Topics: Auditory Pathways; Nitric Oxide; Signal Transduction; Synapses; Synaptic Transmission
PubMed: 34712124
DOI: 10.3389/fncir.2021.759342 -
Current Biology : CB May 2020Neurons are highly specialized cells equipped with a sophisticated molecular machinery for the reception, integration, conduction and distribution of information. The... (Review)
Review
Neurons are highly specialized cells equipped with a sophisticated molecular machinery for the reception, integration, conduction and distribution of information. The evolutionary origin of neurons remains unsolved. How did novel and pre-existing proteins assemble into the complex machinery of the synapse and of the apparatus conducting current along the neuron? In this review, the step-wise assembly of functional modules in neuron evolution serves as a paradigm for the emergence and modification of molecular machinery in the evolution of cell types in multicellular organisms. The pre-synaptic machinery emerged through modification of calcium-regulated large vesicle release, while the postsynaptic machinery has different origins: the glutamatergic postsynapse originated through the fusion of a sensory signaling module and a module for filopodial outgrowth, while the GABAergic postsynapse incorporated an ancient actin regulatory module. The synaptic junction, in turn, is built around two adhesion modules controlled by phosphorylation, which resemble septate and adherens junctions. Finally, neuronal action potentials emerged via a series of duplications and modifications of voltage-gated ion channels. Based on these origins, key molecular innovations are identified that led to the birth of the first neuron in animal evolution.
Topics: Animals; Biological Evolution; Neurons; Synapses; Synaptic Transmission
PubMed: 32428501
DOI: 10.1016/j.cub.2020.04.008 -
Nature Communications Oct 2023Neuronal transmission relies on the regulated secretion of neurotransmitters, which are packed in synaptic vesicles (SVs). Hundreds of SVs accumulate at synaptic...
Neuronal transmission relies on the regulated secretion of neurotransmitters, which are packed in synaptic vesicles (SVs). Hundreds of SVs accumulate at synaptic boutons. Despite being held together, SVs are highly mobile, so that they can be recruited to the plasma membrane for their rapid release during neuronal activity. However, how such confinement of SVs corroborates with their motility remains unclear. To bridge this gap, we employ ultrafast single-molecule tracking (SMT) in the reconstituted system of native SVs and in living neurons. SVs and synapsin 1, the most highly abundant synaptic protein, form condensates with liquid-like properties. In these condensates, synapsin 1 movement is slowed in both at short (i.e., 60-nm) and long (i.e., several hundred-nm) ranges, suggesting that the SV-synapsin 1 interaction raises the overall packing of the condensate. Furthermore, two-color SMT and super-resolution imaging in living axons demonstrate that synapsin 1 drives the accumulation of SVs in boutons. Even the short intrinsically-disordered fragment of synapsin 1 was sufficient to restore the native SV motility pattern in synapsin triple knock-out animals. Thus, synapsin 1 condensation is sufficient to guarantee reliable confinement and motility of SVs, allowing for the formation of mesoscale domains of SVs at synapses in vivo.
Topics: Animals; Synaptic Vesicles; Synapsins; Synapses; Synaptic Transmission; Animals, Genetically Modified
PubMed: 37872159
DOI: 10.1038/s41467-023-42372-6 -
Neuropsychopharmacology : Official... Jan 2023Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the... (Review)
Review
Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre- and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a well-referenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.
Topics: Animals; Humans; Adolescent; Astrocytes; Synaptic Transmission; Synapses; Neurons; Mental Disorders; Neuronal Plasticity
PubMed: 35577914
DOI: 10.1038/s41386-022-01338-w -
Neurobiology of Disease Jan 2022This review provides an overview of the synaptic dysfunction of neuronal circuits and the ensuing behavioral alterations caused by mutations in autism spectrum disorder... (Review)
Review
This review provides an overview of the synaptic dysfunction of neuronal circuits and the ensuing behavioral alterations caused by mutations in autism spectrum disorder (ASD)-linked genes directly or indirectly affecting the postsynaptic neuronal compartment. There are plenty of ASD risk genes, that may be broadly grouped into those involved in gene expression regulation (epigenetic regulation and transcription) and genes regulating synaptic activity (neural communication and neurotransmission). Notably, the effects mediated by ASD-associated genes can vary extensively depending on the developmental time and/or subcellular site of expression. Therefore, in order to gain a better understanding of the mechanisms of disruptions in postsynaptic function, an effort to better model ASD in experimental animals is required to improve standardization and increase reproducibility within and among studies. Such an effort holds promise to provide deeper insight into the development of these disorders and to improve the translational value of preclinical studies.
Topics: Animals; Autism Spectrum Disorder; Epigenesis, Genetic; Neurons; Reproducibility of Results; Synaptic Transmission
PubMed: 34838666
DOI: 10.1016/j.nbd.2021.105564