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Acta Neuropathologica Communications Mar 2023Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains...
Loss of synapses is the most robust pathological correlate of Alzheimer's disease (AD)-associated cognitive deficits, although the underlying mechanism remains incompletely understood. Synaptic terminals have abundant mitochondria which play an indispensable role in synaptic function through ATP provision and calcium buffering. Mitochondrial dysfunction is an early and prominent feature in AD which could contribute to synaptic deficits. Here, using electron microscopy, we examined synapses with a focus on mitochondrial deficits in presynaptic axonal terminals and dendritic spines in cortical biopsy samples from clinically diagnosed AD and age-matched non-AD control patients. Synaptic vesicle density within the presynaptic axon terminals was significantly decreased in AD cases which appeared largely due to significantly decreased reserve pool, but there were significantly more presynaptic axons containing enlarged synaptic vesicles or dense core vesicles in AD. Importantly, there was reduced number of mitochondria along with significantly increased damaged mitochondria in the presynapse of AD which correlated with changes in SV density. Mitochondria in the post-synaptic dendritic spines were also enlarged and damaged in the AD biopsy samples. This study provided evidence of presynaptic vesicle loss as synaptic deficits in AD and suggested that mitochondrial dysfunction in both pre- and post-synaptic compartments contribute to synaptic deficits in AD.
Topics: Humans; Alzheimer Disease; Synapses; Presynaptic Terminals; Mitochondria; Brain
PubMed: 37004141
DOI: 10.1186/s40478-023-01552-7 -
Neuroscience Jun 2016Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies,...
Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases.
Topics: Action Potentials; Animals; Calcium; Cyclin-Dependent Kinase 5; Decapodiformes; Glycogen Synthase Kinase 3 beta; Humans; Inositol 1,4,5-Trisphosphate Receptors; Presynaptic Terminals; Ryanodine Receptor Calcium Release Channel; Synaptic Transmission; tau Proteins
PubMed: 27012611
DOI: 10.1016/j.neuroscience.2016.03.044 -
Developmental Cell Nov 2017Glial cells shape neural circuits by secreting cues that contribute to the spatiotemporal control of connectivity. A new study in Neuron from Farhy-Tselnicker et al.... (Review)
Review
Glial cells shape neural circuits by secreting cues that contribute to the spatiotemporal control of connectivity. A new study in Neuron from Farhy-Tselnicker et al. (2017) shows that the astrocyte-secreted heparan sulfate proteoglycan GPC4 acts on presynaptic terminals to indirectly regulate AMPA receptor clustering and active synapse formation.
Topics: Animals; Astrocytes; Hippocampus; Humans; Motivation; Neurons; Presynaptic Terminals; Synapses
PubMed: 29112849
DOI: 10.1016/j.devcel.2017.10.018 -
Cell Reports Nov 2016Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated...
Here, we show neuronal inactivation-induced presynaptic remodeling and involvement of the mammalian homolog of Diaphanous (mDia) and Rho-associated coiled-coil-containing kinase (ROCK), Rho-regulated modulators of actin and myosin, in this process. We find that social isolation induces inactivation of nucleus accumbens (NAc) neurons associated with elevated anxiety-like behavior, and that mDia in NAc neurons is essential in this process. Upon inactivation of cultured neurons, mDia induces circumferential actin filaments around the edge of the synaptic cleft, which contract the presynaptic terminals in a ROCK-dependent manner. Social isolation induces similar mDia-dependent presynaptic contraction at GABAergic synapses from NAc neurons in the ventral tegmental area (VTA) associated with reduced synaptic efficacy. Optogenetic stimulation of NAc neurons rescues the anxiety phenotype, and injection of a specific ROCK inhibitor, Y-27632, into the VTA reverses both presynaptic contraction and the behavioral phenotype. mDia-ROCK signaling thus mediates actin-dependent presynaptic remodeling in inactivated NAc neurons, which underlies synaptic plasticity in emotional behavioral responses.
Topics: Actin Cytoskeleton; Actins; Aging; Amides; Animals; Anxiety; Behavior, Animal; Brain; Carrier Proteins; Cells, Cultured; Formins; GABAergic Neurons; Mice, Inbred C57BL; Nucleus Accumbens; Optogenetics; Phenotype; Presynaptic Terminals; Pyridines; Social Isolation; Ventral Tegmental Area; rho-Associated Kinases
PubMed: 27880913
DOI: 10.1016/j.celrep.2016.10.088 -
Autophagy Sep 2020Maintaining the integrity and function of the presynaptic neurotransmitter release apparatus is a demanding process for a post-mitotic neuron; the mechanisms behind it...
Maintaining the integrity and function of the presynaptic neurotransmitter release apparatus is a demanding process for a post-mitotic neuron; the mechanisms behind it are still unclear. BSN (bassoon), an active zone scaffolding protein, has been implicated in the control of presynaptic macroautophagy/autophagy, a process we recently showed depends on poly-ubiquitination of synaptic proteins. Moreover, loss of BSN was found to lead to smaller synaptic vesicle (SV) pools and younger pools of the SV protein SV2. Of note, the E3 ligase PRKN/parkin appears to be involved in BSN deficiency-related changes in autophagy levels, as shRNA-mediated knockdown of PRKN counteracts BSN-deficiency and rescues decreased SV protein levels as well as impaired SV recycling in primary cultured neurons. These data imply that BSN and PRKN act in concert to control presynaptic autophagy and maintain presynaptic proteostasis and SV turnover at the physiologically required levels.
Topics: Animals; Autophagosomes; Autophagy; Mice; Nerve Tissue Proteins; Presynaptic Terminals; Synaptic Vesicles; Ubiquitin-Protein Ligases
PubMed: 32718208
DOI: 10.1080/15548627.2020.1801259 -
Cell Reports Mar 2020BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using...
BIN1, a member of the BAR adaptor protein family, is a significant late-onset Alzheimer disease risk factor. Here, we investigate BIN1 function in the brain using conditional knockout (cKO) models. Loss of neuronal Bin1 expression results in the select impairment of spatial learning and memory. Examination of hippocampal CA1 excitatory synapses reveals a deficit in presynaptic release probability and slower depletion of neurotransmitters during repetitive stimulation, suggesting altered vesicle dynamics in Bin1 cKO mice. Super-resolution and immunoelectron microscopy localizes BIN1 to presynaptic sites in excitatory synapses. Bin1 cKO significantly reduces synapse density and alters presynaptic active zone protein cluster formation. Finally, 3D electron microscopy reconstruction analysis uncovers a significant increase in docked and reserve pools of synaptic vesicles at hippocampal synapses in Bin1 cKO mice. Our results demonstrate a non-redundant role for BIN1 in presynaptic regulation, thus providing significant insights into the fundamental function of BIN1 in synaptic physiology relevant to Alzheimer disease.
Topics: Adaptor Proteins, Signal Transducing; Animals; Brain; Excitatory Postsynaptic Potentials; Memory Consolidation; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neurons; Neurotransmitter Agents; Presynaptic Terminals; Recognition, Psychology; SNARE Proteins; Spatial Learning; Tumor Suppressor Proteins
PubMed: 32160554
DOI: 10.1016/j.celrep.2020.02.026 -
The Journal of Neuroscience : the... Feb 2022In presynaptic terminals, membrane-delimited G-mediated presynaptic inhibition is ubiquitous and acts via Gβγ to inhibit Ca entry, or directly at SNARE complexes to...
In presynaptic terminals, membrane-delimited G-mediated presynaptic inhibition is ubiquitous and acts via Gβγ to inhibit Ca entry, or directly at SNARE complexes to inhibit Ca-dependent synaptotagmin-SNARE complex interactions. At CA1-subicular presynaptic terminals, 5-HT and GABA receptors colocalize. GABA receptors inhibit Ca entry, whereas 5-HT receptors target SNARE complexes. We demonstrate in male and female rats that GABA receptors alter P, whereas 5-HT receptors reduce evoked cleft glutamate concentrations, allowing differential inhibition of AMPAR and NMDAR EPSCs. This reduction in cleft glutamate concentration was confirmed by imaging glutamate release using a genetic sensor (iGluSnFR). Simulations of glutamate release and postsynaptic glutamate receptor currents were made. We tested effects of changes in vesicle numbers undergoing fusion at single synapses, relative placement of fusing vesicles and postsynaptic receptors, and the rate of release of glutamate from a fusion pore. Experimental effects of P changes, consistent with GABA receptor effects, were straightforwardly represented by changes in numbers of synapses. The effects of 5-HT receptor-mediated inhibition are well fit by simulated modulation of the release rate of glutamate into the cleft. Colocalization of different actions of GPCRs provides synaptic integration within presynaptic terminals. Train-dependent presynaptic Ca accumulation forces frequency-dependent recovery of neurotransmission during 5-HT receptor activation. This is consistent with competition between Ca-synaptotagmin and Gβγ at SNARE complexes. Thus, stimulus trains in 5-HT receptor agonist unveil dynamic synaptic modulation and a sophisticated hippocampal output filter that itself is modulated by colocalized GABA receptors, which alter presynaptic Ca In combination, these pathways allow complex presynaptic integration. Two G protein-coupled receptors colocalize at presynaptic sites, to mediate presynaptic modulation by Gβγ, but one (a GABA receptor) inhibits Ca entry whereas another (a 5-HT receptor) competes with Ca-synaptotagmin binding to the synaptic vesicle machinery. We have investigated downstream effects of signaling and integrative properties of these receptors. Their effects are profoundly different. GABA receptors alter P leaving synaptic properties unchanged, whereas 5-HT receptors fundamentally change properties of synaptic transmission, modifying AMPAR but sparing NMDAR responses. Coactivation of these receptors allows synaptic integration because of convergence of GABA receptor alteration on Ca and the effect of this altered Ca signal on 5-HT receptor signaling. This presynaptic convergence provides a novel form of synaptic integration.
Topics: Animals; Female; Hippocampus; Male; Organ Culture Techniques; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Synaptic Transmission
PubMed: 34949691
DOI: 10.1523/JNEUROSCI.0035-21.2021 -
Cell Reports Jan 2021Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes...
Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here, we report direct recordings from boutons of neocortical pyramidal neurons and interneurons. Our data reveal rapid and large presynaptic action potentials in layer 5 neurons and fast-spiking interneurons reliably propagating into axon collaterals. For in-depth analyses, we establish boutons of mature cultured neurons as models for excitatory neocortical boutons, demonstrating that the presynaptic spike amplitude is unaffected by potassium channels, homeostatic long-term plasticity, and high-frequency firing. In contrast to the stable amplitude, presynaptic spikes profoundly broaden during high-frequency firing in layer 5 pyramidal neurons, but not in fast-spiking interneurons. Thus, our data demonstrate large presynaptic spikes and fundamental differences between excitatory and inhibitory boutons in the neocortex.
Topics: Electrophysiology; Humans; Neurons; Presynaptic Terminals; Synapses
PubMed: 33440142
DOI: 10.1016/j.celrep.2020.108612 -
EMBO Reports Aug 2022Neuronal presynaptic terminals contain hundreds of neurotransmitter-filled synaptic vesicles (SVs). The morphologically uniform SVs differ in their release competence...
Neuronal presynaptic terminals contain hundreds of neurotransmitter-filled synaptic vesicles (SVs). The morphologically uniform SVs differ in their release competence segregating into functional pools that differentially contribute to neurotransmission. The presynaptic scaffold bassoon is required for neurotransmission, but the underlying molecular mechanisms are unknown. We report that glutamatergic synapses lacking bassoon feature decreased SV release competence and increased resting pool of SVs as assessed by imaging of SV release in cultured neurons. CDK5/calcineurin and cAMP/PKA presynaptic signalling are dysregulated, resulting in an aberrant phosphorylation of their downstream effectors synapsin1 and SNAP25, well-known regulators of SV release competence. An acute pharmacological restoration of physiological CDK5 and cAMP/PKA activity fully normalises the SV pools in neurons lacking bassoon. Finally, we demonstrate that CDK5-dependent regulation of PDE4 activity interacts with cAMP/PKA signalling and thereby controls SV release competence. These data reveal that bassoon organises SV pools in glutamatergic synapses via regulation of presynaptic phosphorylation and cAMP homeostasis and indicate a role of CDK5/PDE4/cAMP axis in the control of neurotransmitter release.
Topics: Nerve Tissue Proteins; Phosphorylation; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35766170
DOI: 10.15252/embr.202153659 -
Neuron Feb 2017Mechanisms regulating the surveillance and clearance of synaptic proteins are not well understood. Intriguingly, the loss of the presynaptic active zone proteins Piccolo...
Mechanisms regulating the surveillance and clearance of synaptic proteins are not well understood. Intriguingly, the loss of the presynaptic active zone proteins Piccolo and Bassoon triggers the loss of synaptic vesicles (SVs) and compromises synaptic integrity. Here we report that the destruction of SVs in boutons lacking Piccolo and Bassoon was associated with the induction of presynaptic autophagy, a process that depended on poly-ubiquitination, but not the E3 ubiquitin ligase Siah1. Surprisingly, gain or loss of function (LOF) of Bassoon alone suppressed or enhanced presynaptic autophagy, respectively, implying a fundamental role for Bassoon in the local regulation of presynaptic autophagy. Mechanistically, Bassoon was found to interact with Atg5, an E3-like ligase essential for autophagy, and to inhibit the induction of autophagy in heterologous cells. Importantly, Atg5 LOF as well as targeting an Atg5-binding peptide derived from Bassoon inhibited presynaptic autophagy in boutons lacking Piccolo and Bassoon, providing insights into the molecular mechanisms regulating presynaptic autophagy.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Nerve Tissue Proteins; Presynaptic Terminals; Rats; Synaptic Vesicles; Ubiquitination
PubMed: 28231469
DOI: 10.1016/j.neuron.2017.01.026