RESUMEN
Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells. Optical elicitation, recording, and modulation of synaptic transmission in behaving mice revealed that activity in presynaptic CA2/3 cells was required for the induction of plasticity in CA1 and, furthermore, that during induction of these place fields in single CA1 cells, synaptic input from CA2/3 onto these same cells was potentiated. These results reveal synaptic implementation of hippocampal behavioral timescale plasticity and define a methodology to resolve synaptic plasticity during learning and memory in behaving mammals.
Asunto(s)
Región CA1 Hipocampal , Hipocampo , Ratones , Animales , Región CA1 Hipocampal/fisiología , Hipocampo/fisiología , Plasticidad Neuronal/fisiología , Aprendizaje/fisiología , Neuronas , Transmisión Sináptica/fisiología , MamíferosRESUMEN
Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , Trastornos Mentales/metabolismo , Plasticidad Neuronal/fisiología , Neuropéptidos/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Homeostasis/fisiología , Humanos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/genética , Neurogénesis/fisiología , Neuropéptidos/genética , Psicotrópicos/farmacología , Psicotrópicos/uso terapéutico , Transmisión Sináptica/efectos de los fármacos , Resultado del TratamientoRESUMEN
RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.
Asunto(s)
Inhibidores de la Angiogénesis/metabolismo , Encéfalo/metabolismo , Neurogénesis , Neuronas/metabolismo , Proteínas Nogo/metabolismo , Receptores Nogo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adipoquinas/metabolismo , Secuencia de Aminoácidos , Animales , Axones/metabolismo , Adhesión Celular , Moléculas de Adhesión Celular Neuronal/metabolismo , Complemento C1q/metabolismo , Dendritas/metabolismo , Glicosilación , Células HEK293 , Células Madre Embrionarias Humanas/metabolismo , Humanos , Ligandos , Ratones Endogámicos C57BL , Red Nerviosa/metabolismo , Polisacáridos/metabolismo , Unión Proteica , Dominios Proteicos , Eliminación de Secuencia , Sinapsis/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca2+-permeable AMPA receptor upregulation, L-type Ca2+ channel activation, enhanced spine Ca2+ transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed â¼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
Asunto(s)
Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Potenciación a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismo , Potenciales de Acción/fisiología , Empalme Alternativo/genética , Empalme Alternativo/fisiología , Animales , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Femenino , Células HEK293 , Homeostasis/fisiología , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/fisiología , Antígeno Ventral Neuro-Oncológico , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Proteínas de Unión al ARN/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sinapsis/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
Dopamine controls essential brain functions through volume transmission. Different from fast synaptic transmission, where neurotransmitter release and receptor activation are tightly coupled by an active zone, dopamine transmission is widespread and may not necessitate these organized release sites. Here, we determine whether striatal dopamine secretion employs specialized machinery for release. Using super resolution microscopy, we identified co-clustering of the active zone scaffolding proteins bassoon, RIM and ELKS in â¼30% of dopamine varicosities. Conditional RIM knockout disrupted this scaffold and, unexpectedly, abolished dopamine release, while ELKS knockout had no effect. Optogenetic experiments revealed that dopamine release was fast and had a high release probability, indicating the presence of protein scaffolds for coupling Ca2+ influx to vesicle fusion. Hence, dopamine secretion is mediated by sparse, mechanistically specialized active zone-like release sites. This architecture supports spatially and temporally precise coding for dopamine and provides molecular machinery for regulation.
Asunto(s)
Axones/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Transmisión Sináptica/fisiología , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cuerpo Estriado/citología , Dopamina/genética , Técnicas de Silenciamiento del Gen , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al GTP rabRESUMEN
Depression is an episodic form of mental illness characterized by mood state transitions with poorly understood neurobiological mechanisms. Antidepressants reverse the effects of stress and depression on synapse function, enhancing neurotransmission, increasing plasticity, and generating new synapses in stress-sensitive brain regions. These properties are shared to varying degrees by all known antidepressants, suggesting that synaptic remodeling could play a key role in depression pathophysiology and antidepressant function. Still, it is unclear whether and precisely how synaptogenesis contributes to mood state transitions. Here, we review evidence supporting an emerging model in which depression is defined by a distinct brain state distributed across multiple stress-sensitive circuits, with neurons assuming altered functional properties, synapse configurations, and, importantly, a reduced capacity for plasticity and adaptation. Antidepressants act initially by facilitating plasticity and enabling a functional reconfiguration of this brain state. Subsequently, synaptogenesis plays a specific role in sustaining these changes over time.
Asunto(s)
Antidepresivos , Depresión , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Plasticidad Neuronal/fisiología , Neuronas , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Developmental myelination is a protracted process in the mammalian brain1. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age2-4. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity5. During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity.
Asunto(s)
Envejecimiento , Vaina de Mielina , Plasticidad Neuronal , Oligodendroglía , Corteza Visual , Animales , Femenino , Masculino , Ratones , Envejecimiento/fisiología , Diferenciación Celular/genética , Espinas Dendríticas/fisiología , Espinas Dendríticas/metabolismo , Vaina de Mielina/metabolismo , Plasticidad Neuronal/fisiología , Oligodendroglía/citología , Oligodendroglía/metabolismo , Oligodendroglía/fisiología , Privación Sensorial/fisiología , Transmisión Sináptica/fisiología , Visión Monocular/fisiología , Corteza Visual/citología , Corteza Visual/fisiología , Corteza Visual/crecimiento & desarrolloRESUMEN
Chemical synapses are commonly known as a structurally and functionally highly diverse class of cell-cell contacts specialized to mediate communication between neurons. They represent the smallest "computational" unit of the brain and are typically divided into excitatory and inhibitory as well as modulatory categories. These categories are subdivided into diverse types, each representing a different structure-function repertoire that in turn are thought to endow neuronal networks with distinct computational properties. The diversity of structure and function found among a given category of synapses is referred to as heterogeneity. The main building blocks for this heterogeneity are synaptic vesicles, the active zone, the synaptic cleft, the postsynaptic density, and glial processes associated with the synapse. Each of these five structural modules entails a distinct repertoire of functions, and their combination specifies the range of functional heterogeneity at mammalian excitatory synapses, which are the focus of this review. We describe synapse heterogeneity that is manifested on different levels of complexity ranging from the cellular morphology of the pre- and postsynaptic cells toward the expression of different protein isoforms at individual release sites. We attempt to define the range of structural building blocks that are used to vary the basic functional repertoire of excitatory synaptic contacts and discuss sources and general mechanisms of synapse heterogeneity. Finally, we explore the possible impact of synapse heterogeneity on neuronal network function.
Asunto(s)
Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Vesículas Sinápticas/fisiología , Animales , Glutamatos/metabolismo , Humanos , Neuronas/fisiologíaRESUMEN
Synapses are highly specialized neuronal structures that are essential for neurotransmission, and they are dynamically regulated throughout the lifetime. Although accumulating evidence indicates that these structures are crucial for information processing and storage in the brain, their precise roles beyond neurotransmission are yet to be fully appreciated. Genetically encoded fluorescent tools have deepened our understanding of synaptic structure and function, but developing an ideal methodology to selectively visualize, label and manipulate synapses remains challenging. Here, we provide an overview of currently available synapse labelling techniques and describe their extension to enable synapse manipulation. We categorize these approaches on the basis of their conceptual bases and target molecules, compare their advantages and limitations and propose potential modifications to improve their effectiveness. These methods have broad utility, particularly for investigating mechanisms of synaptic function and synaptopathy.
Asunto(s)
Sinapsis , Sinapsis/fisiología , Animales , Humanos , Coloración y Etiquetado/métodos , Neuronas/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Transmitter release is a fast Ca(2+)-dependent process triggered in response to membrane depolarization. It involves two major calcium-binding proteins, the voltage-gated calcium channel (VGCC) and the vesicular protein synaptotagmin (syt1). Ca(2+) binding triggers transmitter release with a time response of conformational changes that are too fast to be accounted for by Ca(2+) binding to syt1. In contrast, conformation-triggered release, which engages Ca(2+) binding to VGCC, better accounts for the fast rate of the release process. Here, we summarize findings obtained from heterologous expression systems, neuroendocrine cells, and reconstituted systems, which reveal the molecular mechanism by which Ca(2+) binding to VGCC triggers exocytosis prior to Ca(2+) entry into the cell. This review highlights the molecular aspects of an intramembrane signaling mechanism in which a signal is propagated from the channel transmembrane (TM) domain to the TM domain of syntaxin 1A to trigger transmitter release. It discusses fundamental problems of triggering transmitter release by syt1 and suggests a classification of docked vesicles that might explain synchronous transmitter release, spontaneous release, and facilitation of transmitter release.
Asunto(s)
Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Exocitosis/fisiología , Células Neuroendocrinas/metabolismo , Transmisión Sináptica/fisiología , Sinaptotagminas/metabolismo , Animales , Canales de Calcio/fisiología , Humanos , Modelos Biológicos , Células Neuroendocrinas/fisiologíaRESUMEN
Synaptic plasticity, the activity-dependent change in neuronal connection strength, has long been considered an important component of learning and memory. Computational and engineering work corroborate the power of learning through the directed adjustment of connection weights. Here we review the fundamental elements of four broadly categorized forms of synaptic plasticity and discuss their functional capabilities and limitations. Although standard, correlation-based, Hebbian synaptic plasticity has been the primary focus of neuroscientists for decades, it is inherently limited. Three-factor plasticity rules supplement Hebbian forms with neuromodulation and eligibility traces, while true supervised types go even further by adding objectives and instructive signals. Finally, a recently discovered hippocampal form of synaptic plasticity combines the above elements, while leaving behind the primary Hebbian requirement. We suggest that the effort to determine the neural basis of adaptive behavior could benefit from renewed experimental and theoretical investigation of more powerful directed types of synaptic plasticity.
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Aprendizaje/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Humanos , Neuronas/fisiologíaRESUMEN
Astrocytes regulate multiple aspects of neuronal and synaptic function from development through to adulthood. Instead of addressing each function independently, this review provides a comprehensive overview of the different ways astrocytes modulate neuronal synaptic function throughout life, with a particular focus on recent findings in each area. It includes the emerging functions of astrocytes, such as a role in synapse formation, as well as more established roles, including the uptake and recycling of neurotransmitters. This broad approach covers the many ways astrocytes and neurons constantly interact to maintain the correct functioning of the brain. It is important to consider all of these diverse functions of astrocytes when investigating how astrocyte-neuron interactions regulate synaptic behavior to appreciate the complexity of these ongoing interactions.
Asunto(s)
Astrocitos/fisiología , Proteínas del Tejido Nervioso/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Señalización del Calcio , Comunicación Celular , Ácido Glutámico/fisiología , Humanos , Transporte Iónico , Lípidos/biosíntesis , Neuronas/fisiología , Neurotransmisores/fisiología , Proteínas de Transporte de Neurotransmisores/fisiología , Potasio/metabolismo , Receptores de Neurotransmisores/fisiologíaRESUMEN
Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system.
Asunto(s)
Vaina de Mielina/fisiología , Adenosina Trifosfato/metabolismo , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Axones/fisiología , Sistema Nervioso Central/metabolismo , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Citoesqueleto/ultraestructura , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Glucosa/metabolismo , Humanos , Inflamación , Leucoencefalopatías/metabolismo , Leucoencefalopatías/patología , Ratones , Microscopía Electrónica , Proteínas de la Mielina/fisiología , Plasticidad Neuronal , Oligodendroglía/fisiología , Sistema Nervioso Periférico/metabolismo , Células de Schwann/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Volumetric imaging of synaptic transmission in vivo requires high spatial and high temporal resolution. Shaping the wavefront of two-photon fluorescence excitation light, we developed Bessel-droplet foci for high-contrast and high-resolution volumetric imaging of synapses. Applying our method to imaging glutamate release, we demonstrated high-throughput mapping of excitatory inputs at >1,000 synapses per volume and >500 dendritic spines per neuron in vivo and unveiled previously unseen features of functional synaptic organization in the mouse primary visual cortex.
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Sinapsis , Transmisión Sináptica , Animales , Transmisión Sináptica/fisiología , Ratones , Sinapsis/fisiología , Ácido Glutámico/metabolismo , Corteza Visual/fisiología , Corteza Visual/citología , Espinas Dendríticas/fisiología , Neuronas/fisiología , Corteza Visual Primaria/fisiología , Corteza Visual Primaria/diagnóstico por imagen , Ratones Endogámicos C57BL , Microscopía de Fluorescencia por Excitación Multifotónica/métodosRESUMEN
Synaptic activity imposes large energy demands that are met by local adenosine triphosphate (ATP) synthesis through glycolysis and mitochondrial oxidative phosphorylation. ATP drives action potentials, supports synapse assembly and remodelling, and fuels synaptic vesicle filling and recycling, thus sustaining synaptic transmission. Given their polarized morphological features - including long axons and extensive branching in their terminal regions - neurons face exceptional challenges in maintaining presynaptic energy homeostasis, particularly during intensive synaptic activity. Recent studies have started to uncover the mechanisms and signalling pathways involved in activity-dependent and energy-sensitive regulation of presynaptic energetics, or 'synaptoenergetics'. These conceptual advances have established the energetic regulation of synaptic efficacy and plasticity as an exciting research field that is relevant to a range of neurological disorders associated with bioenergetic failure and synaptic dysfunction.
Asunto(s)
Metabolismo Energético/fisiología , Receptores Presinapticos/metabolismo , Transmisión Sináptica/fisiología , Adenosina Trifosfato/metabolismo , Animales , Glucólisis , Humanos , Vesículas SinápticasRESUMEN
Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at subthreshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical, and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. In perforated patch recordings, activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in both juvenile and adult SPNs. Transcriptomic analysis and pharmacological work suggested that this relatively positive GABAAR reversal potential was not attributable to NKCC1 expression, but rather to HCO3- permeability. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to dendritic iGluR signaling and promoted dendritic spikes. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation for the role of intrastriatal GABAergic circuits.
Asunto(s)
Interneuronas , Receptores de GABA-A , Ratones , Animales , Cuerpo Estriado/fisiología , Neostriado , Transmisión Sináptica/fisiología , Neuronas GABAérgicas/fisiologíaRESUMEN
Spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs) are fundamental electrophysiological events produced by quantal vesicular transmitter release at synapses. Their analysis can provide important information regarding pre- and postsynaptic function. However, the small signal relative to recording noise requires expertise and considerable time for their identification. Furthermore, many mEPSCs smaller than ~8 pA are not well resolved (e.g., those produced at distant synapses or synapses with few receptor channels). Here, we describe an automated approach to detect mEPSCs using a machine learning-based tool. This method, which can be easily generalized to other one-dimensional signals, eliminates inter-observer bias, provides an estimate of its sensitivity and specificity and permits reliable detection of small (e.g., 5 pA) spontaneous unitary synaptic events.
Asunto(s)
Sinapsis , Transmisión Sináptica , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory processing (e.g., sensitivity to input) can be optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient coding. We consider a spike-coding network of leaky integrate-and-fire neurons with synaptic transmission delays. Previously, it was shown that the performance of such networks varies nonmonotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibit some signatures of criticality, namely, scale-free dynamics of the spiking and the presence of crackling noise relation. Our work suggests that two influential, and previously disparate theories of neural processing optimization (efficient coding and criticality) may be intimately related.
Asunto(s)
Potenciales de Acción , Modelos Neurológicos , Red Nerviosa , Neuronas , Transmisión Sináptica , Neuronas/fisiología , Red Nerviosa/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción/fisiología , Encéfalo/fisiología , Humanos , AnimalesRESUMEN
The presynaptic SNARE-complex regulator complexin (Cplx) enhances the fusogenicity of primed synaptic vesicles (SVs). Consequently, Cplx deletion impairs action potential-evoked transmitter release. Conversely, though, Cplx loss enhances spontaneous and delayed asynchronous release at certain synapse types. Using electrophysiology and kinetic modeling, we show that such seemingly contradictory transmitter release phenotypes seen upon Cplx deletion can be explained by an additional of Cplx in the control of SV priming, where its ablation facilitates the generation of a "faulty" SV fusion apparatus. Supporting this notion, a sequential two-step priming scheme, featuring reduced vesicle fusogenicity and increased transition rates into the faulty primed state, reproduces all aberrations of transmitter release modes and short-term synaptic plasticity seen upon Cplx loss. Accordingly, we propose a dual presynaptic function for the SNARE-complex interactor Cplx, one as a "checkpoint" protein that guarantees the proper assembly of the fusion machinery during vesicle priming, and one in boosting vesicle fusogenicity.
Asunto(s)
Sinapsis , Vesículas Sinápticas , Sinapsis/metabolismo , Vesículas Sinápticas/metabolismo , Potenciales de Acción , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood, as neurodevelopment and structural plasticity are tightly linked. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity and synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We report that while both synapse development and activity-induced synaptic remodeling at the fly NMJ require macroautophagy (hereafter referred to as autophagy), bifurcation in the autophagy pathway differentially impacts development and synaptic plasticity. We demonstrate that neuronal activity enhances autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a transsynaptic signaling mechanism modulating synaptic plasticity.