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1.
Front Neural Circuits ; 16: 933201, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937203

RESUMO

In the vertebrate olfactory bulb, reciprocal dendrodendritic interactions between its principal neurons, the mitral and tufted cells, and inhibitory interneurons in the external plexiform layer mediate both recurrent and lateral inhibition, with the most numerous of these interneurons being granule cells. Here, we used recently established anatomical parameters and functional data on unitary synaptic transmission to simulate the strength of recurrent inhibition of mitral cells specifically from the reciprocal spines of rat olfactory bulb granule cells in a quantitative manner. Our functional data allowed us to derive a unitary synaptic conductance on the order of 0.2 nS. The simulations predicted that somatic voltage deflections by even proximal individual granule cell inputs are below the detection threshold and that attenuation with distance is roughly linear, with a passive length constant of 650 µm. However, since recurrent inhibition in the wake of a mitral cell action potential will originate from hundreds of reciprocal spines, the summated recurrent IPSP will be much larger, even though there will be substantial mutual shunting across the many inputs. Next, we updated and refined a preexisting model of connectivity within the entire rat olfactory bulb, first between pairs of mitral and granule cells, to estimate the likelihood and impact of recurrent inhibition depending on the distance between cells. Moreover, to characterize the substrate of lateral inhibition, we estimated the connectivity via granule cells between any two mitral cells or all the mitral cells that belong to a functional glomerular ensemble (i.e., which receive their input from the same glomerulus), again as a function of the distance between mitral cells and/or entire glomerular mitral cell ensembles. Our results predict the extent of the three regimes of anatomical connectivity between glomerular ensembles: high connectivity within a glomerular ensemble and across the first four rings of adjacent glomeruli, substantial connectivity to up to eleven glomeruli away, and negligible connectivity beyond. Finally, in a first attempt to estimate the functional strength of granule-cell mediated lateral inhibition, we combined this anatomical estimate with our above simulation results on attenuation with distance, resulting in slightly narrowed regimes of a functional impact compared to the anatomical connectivity.


Assuntos
Dendritos , Bulbo Olfatório , Animais , Dendritos/fisiologia , Interneurônios/fisiologia , Neurônios , Bulbo Olfatório/fisiologia , Ratos , Sinapses/fisiologia
2.
Int J Mol Sci ; 23(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35955750

RESUMO

Cognitive deficits are core symptoms of schizophrenia but remain poorly addressed by dopamine-based antipsychotic medications. Glutamate abnormalities are implicated in schizophrenia-related cognitive deficits. While the role of the NMDA receptor has been extensively studied, less attention was given to other components that control glutamate homeostasis. Glutamate dynamics at the tripartite synapse include presynaptic and postsynaptic components and are tightly regulated by neuron-astrocyte crosstalk. Here, we delineate the role of glutamate homeostasis at the tripartite synapse in schizophrenia-related cognitive dysfunction. We focus on cognitive domains that can be readily measured in humans and rodents, i.e., working memory, recognition memory, cognitive flexibility, and response inhibition. We describe tasks used to measure cognitive function in these domains in humans and rodents, and the relevance of glutamate alterations in these domains. Next, we delve into glutamate tripartite synaptic components and summarize findings that implicate the relevance of these components to specific cognitive domains. These collective findings indicate that neuron-astrocyte crosstalk at the tripartite synapse is essential for cognition, and that pre- and postsynaptic components play a critical role in maintaining glutamate homeostasis and cognitive well-being. The contribution of these components to cognitive function should be considered in order to better understand the role played by glutamate signaling in cognition and develop efficient pharmacological treatment avenues for schizophrenia treatment-resistant symptoms.


Assuntos
Disfunção Cognitiva , Esquizofrenia , Disfunção Cognitiva/etiologia , Ácido Glutâmico , Homeostase , Humanos , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamento farmacológico , Sinapses/fisiologia
3.
Compr Physiol ; 12(4): 1-36, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35950651

RESUMO

The mammalian neuromuscular junction (NMJ) comprises a presynaptic terminal, a postsynaptic receptor region on the muscle fiber (endplate), and the perisynaptic (terminal) Schwann cell. As with any synapse, the purpose of the NMJ is to transmit signals from the nervous system to muscle fibers. This neural control of muscle fibers is organized as motor units, which display distinct structural and functional phenotypes including differences in pre- and postsynaptic elements of NMJs. Motor units vary considerably in the frequency of their activation (both motor neuron discharge rate and duration/duty cycle), force generation, and susceptibility to fatigue. For earlier and more frequently recruited motor units, the structure and function of the activated NMJs must have high fidelity to ensure consistent activation and continued contractile response to sustain vital motor behaviors (e.g., breathing and postural balance). Similarly, for higher force less frequent behaviors (e.g., coughing and jumping), the structure and function of recruited NMJs must ensure short-term reliable activation but not activation sustained for a prolonged period in which fatigue may occur. The NMJ is highly plastic, changing structurally and functionally throughout the life span from embryonic development to old age. The NMJ also changes under pathological conditions including acute and chronic disease. Such neuroplasticity often varies across motor unit types. © 2022 American Physiological Society. Compr Physiol 12:1-36, 2022.


Assuntos
Neurônios Motores , Junção Neuromuscular , Animais , Fadiga/metabolismo , Fadiga/patologia , Mamíferos , Contração Muscular , Junção Neuromuscular/metabolismo , Sinapses/fisiologia
4.
Sci Rep ; 12(1): 11610, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803955

RESUMO

Neural networks tune synaptic and cellular properties to produce stable activity. One form of homeostatic regulation involves scaling the strength of synapses up or down in a global and multiplicative manner to oppose activity disturbances. In American bullfrogs, excitatory synapses scale up to regulate breathing motor function after inactivity in hibernation, connecting homeostatic compensation to motor behavior. In traditional models of homeostatic synaptic plasticity, inactivity is thought to increase synaptic strength via mechanisms that involve reduced Ca2+ influx through voltage-gated channels. Therefore, we tested whether pharmacological inactivity and inhibition of voltage-gated Ca2+ channels are sufficient to drive synaptic compensation in this system. For this, we chronically exposed ex vivo brainstem preparations containing the intact respiratory network to tetrodotoxin (TTX) to stop activity and nimodipine to block L-type Ca2+ channels. We show that hibernation and TTX similarly increased motoneuron synaptic strength and that hibernation occluded the response to TTX. In contrast, inhibiting L-type Ca2+ channels did not upregulate synaptic strength but disrupted the apparent multiplicative scaling of synaptic compensation typically observed in response to hibernation. Thus, inactivity drives up synaptic strength through mechanisms that do not rely on reduced L-type channel function, while Ca2+ signaling associated with the hibernation environment independently regulates the balance of synaptic weights. Altogether, these results point to multiple feedback signals for shaping synaptic compensation that gives rise to proper network function during environmental challenges in vivo.


Assuntos
Hibernação , Animais , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Rana catesbeiana , Sinapses/fisiologia , Tetrodotoxina/farmacologia
5.
J Integr Neurosci ; 21(4): 112, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35864764

RESUMO

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.


Assuntos
Astrócitos , Neurônios , Astrócitos/fisiologia , Cognição , Humanos , Neurônios/fisiologia , Sinapses/fisiologia
6.
Curr Biol ; 32(14): R786-R788, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35882201

RESUMO

The complicated arbors of neuronal dendrites and axons host synapses, the sites of information transfer and storage. A new paper describes how an important synaptic molecule, Calcium-calmodulin protein kinase 2, gets concentrated at synapses and how its local synthesis is important for memory in the fruit fly.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Sinapses , Axônios/fisiologia , Dendritos/fisiologia , Neurônios/fisiologia , Proteínas Quinases/metabolismo , Sinapses/fisiologia
7.
Int J Neural Syst ; 32(8): 2250036, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35820803

RESUMO

Spiking neural membrane systems are models of computation inspired by the natural functioning of the brain using the concepts of neurons and synapses, and represent a way of building computational systems of a biological inspiration. A variant of such a model, allowing to create new neurons and synapses during the computation, has been considered in the literature to attack computationally hard problems, like problems in the class NP. In this work, we investigate the computational properties of this variant, by proposing three solutions to computationally hard problems, by models with different features, and comparing them with those present in the literature. In particular, we first propose a nondeterministic solution for the NP-complete problem 3-SAT, by a model using dynamic organization of synapses. Then, we propose a deterministic solution for the same problem, by a model using neuron division and dissolution rules. Finally, we show that dissolution rules are not strictly necessary (by accepting a certain amount of slowdown in computing time), and that also problems beyond the class NP can be solved by systems with neuron division alone.


Assuntos
Redes Neurais de Computação , Sinapses , Potenciais de Ação/fisiologia , Encéfalo , Modelos Neurológicos , Neurônios/fisiologia , Sinapses/fisiologia
8.
Sci Rep ; 12(1): 12779, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896554

RESUMO

Microglia contain multiple mechanisms that shape the synaptic landscape during postnatal development. Whether the synaptic changes mediated by microglia reflect the developmental refinement of neuronal responses in sensory cortices, however, remains poorly understood. In postnatal life, the development of increased orientation and spatial frequency selectivity of neuronal responses in primary visual cortex (V1) supports the emergence of high visual acuity. Here, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to rapidly and durably deplete microglia in mice during the juvenile period in which increased orientation and spatial frequency selectivity emerge. Excitatory and inhibitory tuning properties were measured simultaneously using multi-photon calcium imaging in layer II/III of mouse V1. We found that microglia depletion generally increased evoked activity which, in turn, reduced orientation selectivity. Surprisingly, microglia were not required for the emergence of high spatial frequency tuned responses. In addition, microglia depletion did not perturb cortical binocularity, suggesting normal depth processing. Together, our finding that orientation and high spatial frequency selectivity in V1 are differentially supported by microglia reveal that microglia are required normal sensory processing, albeit selectively.


Assuntos
Fator Estimulador de Colônias de Macrófagos/metabolismo , Microglia/patologia , Receptores de Fator Estimulador de Colônias/fisiologia , Sinapses/fisiologia , Córtex Visual/fisiologia , Animais , Camundongos , Microglia/fisiologia , Neurônios/fisiologia , Estimulação Luminosa/métodos , Sinapses/patologia , Córtex Visual/patologia
9.
Sci Rep ; 12(1): 12405, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35859092

RESUMO

Live fluorescence imaging has demonstrated the dynamic nature of dendritic spines, with changes in shape occurring both during development and in response to activity. The structure of a dendritic spine correlates with its functional efficacy. Learning and memory studies have shown that a great deal of the information stored by a neuron is contained in the synapses. High precision tracking of synaptic structures can give hints about the dynamic nature of memory and help us understand how memories evolve both in biological and artificial neural networks. Experiments that aim to investigate the dynamics behind the structural changes of dendritic spines require the collection and analysis of large time-series datasets. In this paper, we present an open-source software called SpineS for automatic longitudinal structural analysis of dendritic spines with additional features for manual intervention to ensure optimal analysis. We have tested the algorithm on in-vitro, in-vivo, and simulated datasets to demonstrate its performance in a wide range of possible experimental scenarios.


Assuntos
Espinhas Dendríticas , Software , Algoritmos , Espinhas Dendríticas/fisiologia , Sinapses/fisiologia , Fatores de Tempo
10.
J Biomed Sci ; 29(1): 51, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821032

RESUMO

BACKGROUND: Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. METHODS: The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. RESULTS: Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. CONCLUSIONS: Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.


Assuntos
Transtorno do Espectro Autista , Receptores de GABA-A , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Ratos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Sinapses/fisiologia , Ácido Valproico , Ácido gama-Aminobutírico
11.
Int J Oncol ; 61(3)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35856439

RESUMO

An increasing body of evidence has become available to reveal the synaptic and functional integration of glioma into the brain network, facilitating tumor progression. The novel discovery of glioma­neuronal interactions has fundamentally challenged our understanding of this refractory disease. The present review aimed to provide an overview of how the neuronal activities function through synapses, neurotransmitters, ion channels, gap junctions, tumor microtubes and neuronal molecules to establish communications with glioma, as well as a simplified explanation of the reciprocal effects of crosstalk on neuronal pathophysiology. In addition, the current state of therapeutic avenues targeting critical factors involved in glioma­euronal interactions is discussed and an overview of clinical trial data for further investigation is provided. Finally, newly emerging technologies, including immunomodulation, a neural stem cell­based delivery system, optogenetics techniques and co­culture of neuron organoids and glioma, are proposed, which may pave a way towards gaining deeper insight into both the mechanisms associated with neuron­ and glioma­communicating networks and the development of therapeutic strategies to target this currently lethal brain tumor.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/patologia , Glioma/terapia , Humanos , Neurônios , Optogenética/métodos , Sinapses/fisiologia
12.
Learn Mem ; 29(8): 192-202, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35882501

RESUMO

Local protein synthesis at synapses can provide a rapid supply of proteins to support synaptic changes during consolidation of new memories, but its role in the maintenance or updating of established memories is unknown. Consolidation requires new protein synthesis in the period immediately following learning, whereas established memories are resistant to protein synthesis inhibitors. We have previously reported that polyribosomes are up-regulated in the lateral amygdala (LA) during consolidation of aversive-cued Pavlovian conditioning. In this study, we used serial section electron microscopy reconstructions to determine whether the distribution of dendritic polyribosomes returns to baseline during the long-term memory phase. Relative to control groups, long-term memory was associated with up-regulation of polyribosomes throughout dendrites, including in dendritic spines of all sizes. Retrieval of a consolidated memory by presentation of a small number of cues induces a new, transient requirement for protein synthesis to maintain the memory, while presentation of a large number of cues results in extinction learning, forming a new memory. One hour after retrieval or extinction training, the distribution of dendritic polyribosomes was similar except in the smallest spines, which had more polyribosomes in the extinction group. Our results demonstrate that the effects of learning on dendritic polyribosomes are not restricted to the transient translation-dependent phase of memory formation. Cued Pavlovian conditioning induces persistent synapse strengthening in the LA that is not reversed by retrieval or extinction, and dendritic polyribosomes may therefore correlate generally with synapse strength as opposed to recent activity or transient translational processes.


Assuntos
Condicionamento Clássico , Sinapses , Condicionamento Clássico/fisiologia , Extinção Psicológica , Memória de Longo Prazo , Polirribossomos , Sinapses/fisiologia , Regulação para Cima
13.
ACS Appl Mater Interfaces ; 14(31): 35917-35926, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35882423

RESUMO

Brain-inspired intelligent systems demand diverse neuromorphic devices beyond simple functionalities. Merging biomimetic sensing with weight-updating capabilities in artificial synaptic devices represents one of the key research focuses. Here, we report a multiresponsive synapse device that integrates synaptic and optical-sensing functions. The device adopts vertically stacked graphene/h-BN/WSe2 heterostructures, including an ultrahigh-mobility readout layer, a weight-control layer, and a dual-stimuli-responsive layer. The unique structure endows synapse devices with excellent synaptic plasticity, short response time (3 µs), and excellent optical responsivity (105 A/W). To demonstrate the application in neuromorphic computing, handwritten digit recognition was simulated based on an unsupervised spiking neural network (SNN) with a precision of 90.89%, well comparable with the state-of-the-art results. Furthermore, multiterminal neuromorphic devices are demonstrated to mimic dendritic integration and photoswitching logic. Different from other synaptic devices, the research work validates multifunctional integration in synaptic devices, supporting the potential fusion of sensing and self-learning in neuromorphic networks.


Assuntos
Redes Neurais de Computação , Sinapses , Biomimética , Aprendizagem , Plasticidade Neuronal , Sinapses/fisiologia
14.
Hippocampus ; 32(8): 610-623, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35851733

RESUMO

Rett syndrome is a leading cause of intellectual disability in females primarily caused by loss of function mutations in the transcriptional regulator MeCP2. Loss of MeCP2 leads to a host of synaptic phenotypes that are believed to underlie Rett syndrome pathophysiology. Synaptic deficits vary by brain region upon MeCP2 loss, suggesting distinct molecular alterations leading to disparate synaptic outcomes. In this study, we examined the contribution of MeCP2's newly described role in miRNA regulation to regional molecular and synaptic impairments. Two miRNAs, miR-101a and miR-203, were identified and confirmed as upregulated in MeCP2 KO mice in the hippocampus and cortex, respectively. miR-101a overexpression in hippocampal cultures led to opposing effects at excitatory and inhibitory synapses and in spontaneous and evoked neurotransmission, revealing the potential for a single miRNA to broadly regulate synapse function in the hippocampus. These results highlight the importance of regional alterations in miRNA expression and the specific impact on synaptic function with potential implications for Rett syndrome.


Assuntos
MicroRNAs , Síndrome de Rett , Animais , Feminino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/genética
15.
Science ; 377(6605): 539-543, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35901152

RESUMO

Nanoscale ionic programmable resistors for analog deep learning are 1000 times smaller than biological cells, but it is not yet clear how much faster they can be relative to neurons and synapses. Scaling analyses of ionic transport and charge-transfer reaction rates point to operation in the nonlinear regime, where extreme electric fields are present within the solid electrolyte and its interfaces. In this work, we generated silicon-compatible nanoscale protonic programmable resistors with highly desirable characteristics under extreme electric fields. This operation regime enabled controlled shuttling and intercalation of protons in nanoseconds at room temperature in an energy-efficient manner. The devices showed symmetric, linear, and reversible modulation characteristics with many conductance states covering a 20× dynamic range. Thus, the space-time-energy performance of the all-solid-state artificial synapses can greatly exceed that of their biological counterparts.


Assuntos
Aprendizado Profundo , Prótons , Neurônios/fisiologia , Silício , Sinapses/fisiologia
16.
J Neurosci ; 42(32): 6211-6220, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35790402

RESUMO

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.


Assuntos
Núcleo Coclear , Óxido Nítrico , Animais , Vias Auditivas/metabolismo , Nervo Coclear/fisiologia , Núcleo Coclear/fisiologia , Feminino , Masculino , Camundongos , Plasticidade Neuronal/fisiologia , Óxido Nítrico/metabolismo , Potássio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
17.
Dev Cell ; 57(15): 1802-1816.e4, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35809561

RESUMO

Synapse formation is locally determined by transmembrane proteins, yet synaptic material is synthesized remotely and undergoes processive transport in axons. How local synaptogenic signals intercept synaptic cargo in transport to promote its delivery and synapse formation is unknown. We found that the control of synaptic cargo delivery at microtubule (MT) minus ends mediates pro- and anti-synaptogenic activities of presynaptic neurexin and frizzled in C. elegans and identified the atypical kinesin VAB-8/KIF26 as a key molecule in this process. VAB-8/KIF26 levels at synaptic MT minus ends are controlled by frizzled and neurexin; loss of VAB-8 mimics neurexin mutants or frizzled hyperactivation, and its overexpression can rescue synapse loss in these backgrounds. VAB-8/KIF26 is required for the synaptic localization of other minus-end proteins and promotes the pausing of retrograde transport to allow delivery to synapses. Consistently, reducing retrograde transport rescues synapse loss in vab-8 and neurexin mutants. These results uncover a mechanistic link between synaptogenic signaling and axonal transport.


Assuntos
Transporte Axonal , Caenorhabditis elegans , Animais , Axônios/metabolismo , Caenorhabditis elegans/genética , Microtúbulos/metabolismo , Sinapses/fisiologia
18.
J Physiol ; 600(16): 3865-3896, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35852108

RESUMO

Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within-train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long-term potentiation, which increases release by LPP terminals, enhanced within-train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3-CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three-pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically. KEY POINTS: The lateral perforant path (LPP)-dentate gyrus (DG) synapse operates as a low-pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed. Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds). Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses. LPP frequency filtering is modified by the unique presynaptic long-term potentiation at this synapse. Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP-DG frequency filtering.


Assuntos
Cálcio , Via Perfurante , Animais , Giro Denteado/fisiologia , Estimulação Elétrica , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Camundongos , Via Perfurante/fisiologia , Sinapses/fisiologia
19.
Phys Rev E ; 105(6-1): 064407, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35854532

RESUMO

The lateral diffusion and trapping of neurotransmitter receptors within the postsynaptic membrane of a neuron play a key role in determining synaptic strength and plasticity. Trapping is mediated by the reversible binding of receptors to scaffolding proteins (slots) within a synapse. In this paper we introduce a method for analyzing the transient dynamics of proximal axodendritic synapses in a diffusion-trapping model of receptor trafficking. Given a population of spatially distributed synapses, each of which has a fixed number of slots, we calculate the rate of relaxation to the steady-state distribution of bound slots (synaptic weights) in terms of a set of local accumulation times. Assuming that the rates of exocytosis and endocytosis are sufficiently slow, we show that the steady-state synaptic weights are independent of each other (purely local). On the other hand, the local accumulation time of a given synapse depends on the number of slots and the spatial location of all the synapses, indicating a form of transient heterosynaptic plasticity. This suggests that local accumulation time measurements could provide useful information regarding the distribution of synaptic weights within a dendrite.


Assuntos
Neurônios , Sinapses , Difusão , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de Neurotransmissores/metabolismo , Sinapses/fisiologia , Membranas Sinápticas/metabolismo
20.
BMC Biol ; 20(1): 158, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35804361

RESUMO

BACKGROUND: In a broad variety of species, muscle contraction is controlled at the neuromuscular junction (NMJ), the peripheral synapse composed of a motor nerve terminal, a muscle specialization, and non-myelinating terminal Schwann cells. While peripheral nerve damage leads to successful NMJ reinnervation in animal models, muscle fiber reinnervation in human patients is largely inefficient. Interestingly, some hallmarks of NMJ denervation and early reinnervation in murine species, such as fragmentation and poly-innervation, are also phenotypes of aged NMJs or even of unaltered conditions in other species, including humans. We have reasoned that rather than features of NMJ decline, such cellular responses could represent synaptic adaptations to accomplish proper functional recovery. Here, we have experimentally tackled this idea through a detailed comparative study of the short- and long-term consequences of irreversible (chronic) and reversible (partial) NMJ denervation in the convenient cranial levator auris longus muscle. RESULTS: Our findings reveal that irreversible muscle denervation results in highly fragmented postsynaptic domains and marked ectopic acetylcholine receptor clustering along with significant terminal Schwann cells sprouting and progressive detachment from the NMJ. Remarkably, even though reversible nerve damage led to complete reinnervation after 11 days, we found that more than 30% of NMJs are poly-innervated and around 65% of postsynaptic domains are fragmented even 3 months after injury, whereas synaptic transmission is fully recovered two months after nerve injury. While postsynaptic stability was irreversibly decreased after chronic denervation, this parameter was only transiently affected by partial NMJ denervation. In addition, we found that a combination of morphometric analyses and postsynaptic stability determinations allows discriminating two distinct forms of NMJ fragmentation, stable-smooth and unstable-blurred, which correlate with their regeneration potential. CONCLUSIONS: Together, our data unveil that reversible nerve damage imprints a long-lasting reminiscence in the NMJ that results in the rearrangement of its cellular components. Instead of being predictive of NMJ decline, these traits may represent an efficient adaptive response for proper functional recovery. As such, these features are relevant targets to be considered in strategies aimed to restore motor function in detrimental conditions for peripheral innervation.


Assuntos
Regeneração Nervosa , Traumatismos dos Nervos Periféricos , Animais , Camundongos , Regeneração Nervosa/fisiologia , Junção Neuromuscular/fisiologia , Células de Schwann/fisiologia , Sinapses/fisiologia
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