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Synapses in the brain are highly noisy, which leads to a large trial-by-trial variability. Given how costly synapses are in terms of energy consumption these high levels of noise are surprising. Here we propose that synapses use their noise to represent uncertainties about the activity of the post-synaptic neuron. To show this we utilize the free-energy principle (FEP), a well-established theoretical framework to describe the ability of organisms to self-organize and survive in uncertain environments. This principle provides insights on multiple scales, from high-level behavioral functions such as attention or foraging, to the dynamics of single microcircuits in the brain, suggesting that the FEP can be used to describe all levels of brain function. The synapse-centric account of the FEP that is pursued here, suggests that synapses form an internal model of the somatic membrane dynamics, being updated by a synaptic learning rule that resembles experimentally well-established LTP/LTD mechanisms. This approach entails that a synapse utilizes noisy processes like stochastic synaptic release to also encode its uncertainty about the state of the somatic potential. Although each synapse strives for predicting the somatic dynamics of its neuron, we show that the emergent dynamics of many synapses in a neuronal network resolve different learning problems such as pattern classification or closed-loop control in a dynamic environment. Hereby, synapses coordinate their noise processes to represent and utilize uncertainties on the network level in behaviorally ambiguous situations.

Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The structure of the pre-fusion state of the SNARE/complexin-1/synaptotagmin-1 synaptic protein complex suggests a new model for the initiation of fast Ca2+-triggered membrane fusion. Functional studies have revealed roles of the essential factors Munc18 and Munc13, demonstrating that a part of their function involves the proper assembly of synaptic protein complexes. Near-atomic resolution structures of the NSF/αSNAP/SNARE complex provide first glimpses of the molecular machinery that disassembles the SNARE complex during the synaptic vesicle cycle. These structures show how this machinery captures the SNARE substrate and provide clues as to a possible processing mechanism.

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as “synaptopathy.” Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.

Recent advances in 2-photon calcium-imaging in awake mice have made it possible to study the effect of different behavioural states on cortical circuitry. Many studies assume that somatic activity can be used as a measure for neuronal output. We set out to test the validity of this assumption by comparing somatic activity with the pre-synaptic activity of VIP (Vasoactive intestinal peptide)- and SST (Somatostatin)-positive interneurons in layer 2/3 of the primary visual cortex (V1). We used mice expressing genetically encoded calcium indicators in VIP/SST-interneurons across the whole cell (VIP/SST:GCaMP6f) or confined to pre-synapses (VIP/SST:SyGCaMP5). Mice were exposed to a full-field visual stimulation protocol consisting of 60-second-long presentations of moving Gabor gratings (0.04 cpd, 2 Hz) alternated by 30 seconds of grey screen. During imaging, mice were placed on an air-suspended Styrofoam ball, allowing them to run voluntarily. We compared neural activity during three 4-second time-windows: Before visual stimulation (−4 to 0 sec), during the initial onset (1 to 5 sec) and at the end of the stimulation (56 to 60 sec.). These were further compared while the mice were stationary and while they were voluntarily locomoting. Unlike VIP-somas, VIP-pre-synapses showed strong suppressive responses to the visual stimulus. Furthermore, VIP-somas were positively correlated with locomotion, whereas in VIP-synapses we observed a split between positive and negative correlations. In addition, a similar but weaker distinction was found between SST-somas and pre-synapses. The excitatory effect of locomotion in VIP-somas increased over the course of the visual stimulus but this property was only shared with the positively correlated VIP-pre-synapses. The remaining negatively correlated pre-synapses showed no relation to the overall activity of the Soma. Our results suggest that when making statements about the involvement of interneurons in V1 layer 2/3 circuitry it is crucial to measure from synaptic terminals as well as from somas.

Anticonvulsants targeting KMechanisms underlying epileptogenesis with A-channel inhibition and antiepileptic actions of A-channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches.Pre-synaptic KTrans-synaptic voltage-dependent A-channels serve as a biophysical-biochemical transducer responsible for a novel form of synaptic plasticity. Such a network-level switch into and out of the oscillatory mode may underlie a wide scope of telencephalic information processing or, at its extreme, epileptic seizures. A-channels thus constitute a potential target of antiepileptic therapy.

To investigate whether there are more quantitative pre-synaptic ribbons formed in the cochlear region corresponding to middle-frequency in cochlea of mice.Counts of pre-synaptic ribbons were performed using immunostaining and laser confocal microscopy. Hearing thresholds and function of ribbon synapses were estimated by auditory brain response (ABR) and compound action potential (CAP). Cochlear mapping has been achieved to match the frequencies and corresponding regions along the cochlear spiral.The number of pre-synaptic ribbons in per inner hair cell (IHC) has been found to increase gradually from the base turn, the maximal quantity appeared at the region of 50-70% from the apex. Next, ABR thresholds showed that there was the lowest ABR threshold in the frequency around 8-16 kHz, corresponding to the region of 50-70% from the apex according to the cochlear mapping. Further, CAP amplitudes were estimated, and the maximal value identified at the same frequency (8-16 kHz).Maximal number of pre-synaptic ribbons is formed in the cochlear region of middle frequency in mice, coupling with the lowest ABR threshold and highest CAP amplitudes. Our study shows that the middle frequency (8-16 kHz) could be the most sensitive region to sound stimuli in mice.

Bernstein Conference 2021 abstract. http://bernstein-conference.de

International audience; This is an Editorial Highlight of a manuscript by Oldani et al. (2020) (Oldani et al. 2020) in the current issue of the Journal of Neurochemistry, in which the authors describe synaptoPAC, a new optogenetic tool. SynaptoPAC is targeted to pre-synaptic compartments and can be used for light-induced increase of the levels of cAMP. Pre-synaptic plasticity, defined as activity-dependent modulation of neurotransmitter release, occurs over a variety of time scales. At a subset of synapses in the brain, long-term forms of pre-synaptic facilitation depend on an increase in the levels of cAMP. Light-induced modulation of cAMP at synapses expressing cAMP-dependent facilitation, has the great potential to mimic pre-synaptic plasticity at genetically targeted synapses. Therefore, synaptoPAC constitutes a powerful tool to study the role of pre-synaptic potentiation in the activity of selected neuronal circuits in relation to behaving animals with a high temporal and spatial precision.

Virtually all rodent neuroendocrine corticotropin-releasing-hormone (CRH) neurons are in the dorsal medial parvicellular (mpd) part of the paraventricular nucleus of the hypothalamus (PVH). They form the final common pathway for adrenocortical stress responses. Their activity is controlled by sets of GABA-, glutamate-, and catecholamine-containing inputs arranged in an interactive pre-motor network. Defining the nature and arrangement of these inputs can help clarify how stressor type and intensity information is conveyed to neuroendocrine neurons. Here we use immunohistochemistry with high-resolution 3-dimensional image analyses to examine the arrangement of single- and co-occurring GABA, glutamate, and catecholamine markers in synaptophysin-defined pre-synaptic terminals in the PVHmpd of unstressed rats and Crh-IRES-Cre;Ai14 transgenic mice: respectively, vesicular glutamate transporter 2 (VGluT2), vesicular GABA transporter (VGAT), dopamine β-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT). Just over half of all PVHmpd pre-synaptic terminals contain VGAT, with slightly less containing VGluT2. The vast majority of terminal appositions with mouse CRH neurons occur non-somatically. However, there are significantly more somatic VGAT than VGluT2 appositions. In the rat PVHmpd, about five times as many pre-synaptic terminals contain PNMT than DBH only. However, because epinephrine release has never been detected in the PVH, PNMT terminals may functionally be noradrenergic not adrenergic. PNMT and VGluT2 co-occur in some pre-synaptic terminals indicating the potential for co-transmission of glutamate and norepinephrine. Collectively, these results provide a structural basis for how GABA/glutamate/catecholamine interactions enable adrenocortical responses to fast-onset interosensory stimuli, and more broadly, how combinations of PVH neurotransmitters and neuromodulators interact dynamically to control adrenocortical activity.

Made available in DSpace on 2021-06-25T10:54:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-15 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) In vertebrates, muscle activity is dependent on acetylcholine (ACh) released from neuromuscular junctions (NMJs), and changes in cholinergic neurotransmission are linked to a variety of neuromuscular diseases, including congenital myasthenic syndromes (CMS). The storage and release of ACh depends on the activity of the Vesicular Acetylcholine Transporter (VAChT), a rate-limiting step for cholinergic neurotransmission whose loss of function mutations was shown to cause human congenital myasthenia. However, we know much less about increased VAChT activity, due to copy number variations, for example. Therefore, here we investigated the impact of increased VAChT expression and consequently ACh levels at the synaptic cleft of the diaphragm NMJs. We analyzed structure and function of nerve and muscles from a mouse model of cholinergic hyperfunction (ChAT-ChR2-EYFP) with increased expression of VAChT. Our results showed a significant increase of ACh released under evoked stimuli. However, we observed deleterious changes in synaptic vesicles cycle (impaired endocytosis and decrease in vesicles number), together with structural alterations of NMJs. Interestingly, ultrastructure analyses showed that synaptic vesicles from ChAT-ChR2-EYFP mice NMJs were larger, which might be related to increased ACh load. We also observed that these larger synaptic vesicles were less rounded in comparison with control. Finally, we showed that ChAT-ChR2-EYFP mice NMJs have compromised safety factor, possible due to the structural alterations we described. These findings reveal that physiological cholinergic activity is important to maintain the structure and function of the neuromuscular system and help to understand some of the neuromuscular adverse effects experienced by chronically increased NMJ neurotransmission, such as individuals treated with cholinesterase inhibitors. Departamento de Morfologia ICB Universidade Federal de Minas Gerais Departamento de Fisiologia e Biofísica ICB Universidade Federal de Minas Gerais Departamento de Farmacologia ICB Universidade Federal de Minas Gerais Departamento de Ciências Básicas da Vida Instituto de Ciências da Vida Universidade Federal de Juiz de Fora Campus Governador Valadares UFJF Departamento de Farmacologia Instituto de Biociências UNESP, Distrito de Rubião Jr. Robarts Research Institute and Department of Physiology and Pharmacology and Anatomy & Cell Biology University of Western Ontario Departamento de Medicina Faculdade Ciências Médicas de Minas Gerais FCMMG Departamento de Farmacologia Instituto de Biociências UNESP, Distrito de Rubião Jr. CNPq: 150567/2019-7 CNPq: 401071/2014-6 FAPEMIG: APQ-00092-18

Although the output of the lateral habenula (LHb) controls the activity of midbrain dopaminergic and serotonergic systems, which are implicated in the pathophysiology of anxiety, it is not known how blockade of GABA

The Rho kinase (ROCK) signaling pathway is an attractive therapeutic target in neurodegeneration since it has been linked to the prevention of neuronal death and neurite regeneration. The isoquinoline derivative fasudil is a potent ROCK inhibitor, which is already approved for chronic clinical treatment in humans. However, the effects of chronic fasudil treatments on neuronal function are still unknown. We analyzed here chronic fasudil treatment in primary rat hippocampal cultures. Neurons were stimulated with 20 Hz field stimulation and we investigated pre-synaptic mechanisms and parameters regulating synaptic transmission after fasudil treatment by super resolution stimulated emission depletion (STED) microscopy, live-cell fluorescence imaging, and western blotting. Fasudil did not affect basic synaptic function or the amount of several synaptic proteins, but it altered the chronic dynamics of the synaptic vesicles. Fasudil reduced the proportion of the actively recycling vesicles, and shortened the vesicle lifetime, resulting overall in a reduction of the synaptic response upon stimulation. We conclude that fasudil does not alter synaptic structure, accelerates vesicle turnover, and decreases the number of released vesicles. This broadens the known spectrum of effects of this drug, and suggests new potential clinical uses.

AimsEfficient synaptic communication is crucial to maintain healthy behavioural and cognitive processes. Individuals affected by schizophrenia present behavioural symptoms and alterations in decision-making, suggesting altered synaptic integrity as the support of the illness. It is currently unknown how this synaptic change is mediated in schizophrenia, but microglia have been proposed to act as the culprit, actively removing synapses pathologically. Here, we aimed to explore the interaction between microglia and synaptic uptake in human post-mortem tissue.MethodsWe assessed microglial activation and synaptic internalisation by microglia in a post-mortem human tissue of 10 control and 10 schizophrenia cases. Immunohistochemistry was performed to identify microglia (Iba1 and CD68) and the presynaptic terminals (synapsin I).ResultsWe found no difference in microglial expression, nor a difference in pre-synaptic protein level phagocyted by microglia between the two groups.ConclusionsOur findings are consistent with the brain imaging studies in schizophrenia implying that microglia play a role mainly during the early phases of the disease, by example in active synapse remodelling, which is not detected in the chronic stage of the illness.