scholarly journals Activity-dependent trafficking of lysosomes in dendrites and dendritic spines

2017 ◽  
Vol 216 (8) ◽  
pp. 2499-2513 ◽  
Author(s):  
Marisa S. Goo ◽  
Laura Sancho ◽  
Natalia Slepak ◽  
Daniela Boassa ◽  
Thomas J. Deerinck ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Synaptic Activity ◽  
Synaptic Membrane ◽  
Dependent Manner ◽  
Two Photon ◽  
Acid Type ◽  
Cytoskeletal Dynamics ◽  
And Function ◽  
Actin Cytoskeletal Dynamics ◽  
Activity Dependent

In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins.

scholarly journals Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0128241 ◽  
Author(s):  
Jian-Hua Chen ◽  
Yves Kellner ◽  
Marta Zagrebelsky ◽  
Matthias Grunwald ◽  
Martin Korte ◽  
...  
Keyword(s):  
Actin Filament ◽  
Dendritic Spines ◽  
Photon Correlation Spectroscopy ◽  
Correlation Spectroscopy ◽  
Photon Correlation ◽  
Two Photon ◽  
Dependent Growth ◽  
Activity Dependent

scholarly journals Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study

2016 ◽  
Vol 2016 ◽  
pp. 1-30 ◽  
Author(s):  
Maurizio De Pittà ◽  
Nicolas Brunel
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Release ◽  
Spike Timing ◽  
Biophysical Model ◽  
Dependent Manner ◽  
Inward Currents ◽  
Functional Relevance ◽  
And Function ◽  
Activity Dependent

Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol.

scholarly journals Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

2018 ◽  
Author(s):  
Erica C. Dresselhaus ◽  
Matthew C.H. Boersma ◽  
Mollie K. Meffert
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dendritic Spines ◽  
Brain Plasticity ◽  
Spatial Localization ◽  
Synaptic Activity ◽  
Wild Type ◽  
Spine Development ◽  
Response Expression ◽  
Activity Dependent

ABSTRACTLong-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor kappa B (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment (ΔSEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or ΔSEp65 both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not ΔSEp65, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses.SIGNIFICANCE STATEMENTExtensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus-specificity to gene regulation, insuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.

scholarly journals Neurexin-Neuroligin Synaptic Complex Regulates Schizophrenia-Related DISC1/Kal-7/Rac1 “Signalosome”

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Sylwia Owczarek ◽  
Marie Louise Bang ◽  
Vladimir Berezin
Keyword(s):  
Central Nervous System ◽  
Cell Adhesion Molecules ◽  
Synaptic Membranes ◽  
Dependent Manner ◽  
Related Protein ◽  
Synaptic Complex ◽  
The Central Nervous System ◽  
And Function ◽  
Activity Dependent ◽  
The Brain

Neurexins (NXs) and neuroligins (NLs) are cell adhesion molecules that are localized at opposite sites of synaptic membranes. They interact with each other to promote the assembly, maintenance, and function of synapses in the central nervous system. Both NX and NL are cleaved from a membrane-attached intracellular domain in an activity-dependent manner, generating the soluble ectodomain of NX or NL. Expression of theNX1andNX3genes in the brain appears to be regulated by a schizophrenia-related protein, DISC1. Here, we show that soluble ecto-NX1βcan regulate the expression of DISC1 and induce signaling downstream of DISC1. We also show that NL1 binds to a well-characterized DISC1 interaction partner, Kal-7, and this interaction can be compromised by DISC1. Our results indicate that the NX/NL synaptic complex is intrinsically involved in the regulation of DISC1 function, thus contributing to a better understanding of the pathology of schizophrenia.

scholarly journals Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C

2010 ◽  
Vol 189 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Chieh Hsu ◽  
Yuichi Morohashi ◽  
Shin-ichiro Yoshimura ◽  
Natalia Manrique-Hoyos ◽  
SangYong Jung ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Multivesicular Bodies ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Gtpase Activating Proteins ◽  
The Central Nervous System ◽  
And Function ◽  
Endosomal Vesicles ◽  
Activity Dependent

Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron–glia communication. These exosomes are small vesicles with a diameter of 50–100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A–C regulate exosome secretion in a catalytic activity–dependent manner. We show that Rab35 is the target of TBC1D10A–C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.

scholarly journals Synaptic activity controls autophagic vacuole motility and function in dendrites

2021 ◽  
Vol 220 (6) ◽  
Author(s):  
Vineet Vinay Kulkarni ◽  
Anip Anand ◽  
Jessica Brandt Herr ◽  
Christina Miranda ◽  
Maria Chalokh Vogel ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Degradation Pathway ◽  
Autophagic Vacuole ◽  
Synaptic Activity ◽  
Lysosomal Degradation ◽  
Autophagy Pathway ◽  
Dynamics And Function ◽  
And Function ◽  
Activity Dependent ◽  
Stimulation Of

Macroautophagy (hereafter “autophagy”) is a lysosomal degradation pathway that is important for learning and memory, suggesting critical roles for autophagy at the neuronal synapse. Little is known, however, about the molecular details of how autophagy is regulated with synaptic activity. Here, we used live-cell confocal microscopy to define the autophagy pathway in primary hippocampal neurons under various paradigms of synaptic activity. We found that synaptic activity regulates the motility of autophagic vacuoles (AVs) in dendrites. Stimulation of synaptic activity dampens AV motility, whereas silencing synaptic activity induces AV motility. Activity-dependent effects on dendritic AV motility are local and reversible. Importantly, these effects are compartment specific, occurring in dendrites and not in axons. Most strikingly, synaptic activity increases the presence of degradative autolysosomes in dendrites and not in axons. On the basis of our findings, we propose a model whereby synaptic activity locally controls AV dynamics and function within dendrites that may regulate the synaptic proteome.

scholarly journals Activity-dependent expression of reporter proteins at dendritic spines for synaptic activity mapping and optogenetic stimulation

2016 ◽  
Author(s):  
Francesco Gobbo ◽  
Laura Marchetti ◽  
Claudia Alia ◽  
Stefano Luin ◽  
Antonino Cattaneo
Keyword(s):  
Dendritic Spines ◽  
Cognitive Disorders ◽  
Synaptic Activity ◽  
Regulatory Sequences ◽  
Synaptic Connections ◽  
Optogenetic Stimulation ◽  
Reporter Proteins ◽  
Activity Dependent ◽  
The Brain ◽  
Spine Number

Increasing evidence points to the importance of dendritic spines in the formation and allocation of memories, and alterations of spine number and physiology are associated to memory and cognitive disorders. Synaptic connections and pathways constitute the physical substrate that conveys information in the brain, and different combinations of active synaptic connections are believed to be responsible for the encoding of specific memories. In addition, modifications of the activity of such subsets of synapses are believed to be crucial for memory establishment, but a way to directly test this hypothesis, by selectively controlling the activity of potentiated spines, is currently lagging behind. Therefore it would be important to develop methods to tag active synapses for mapping functionally active connections and to selectively stimulate or interfere with active synapses. Here we introduce an approach to express light-sensitive membrane channels at synapses in an activity-dependent way by means of RNA and protein regulatory sequences. This approach is based on the local expression of reporter proteins, including optogenetic probes, at activated synapses and will allow the mapping of previously active synapses and the re-activation of the neuron only at these sites. This will allow extending the investigation of memory processes beyond the current neuron tagging technologies, whose resolution is limited at the cellular scale. Thus, it will be possible to unveil and recall the synaptic engram out of the global set of synapses.

scholarly journals Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

2017 ◽  
Author(s):  
Oliver H. Miller ◽  
Andreas Bruns ◽  
Imen Ben Ammar ◽  
Thomas Mueggler ◽  
Benjamin J. Hall
Keyword(s):  
Viral Vectors ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Prefrontal Cortical ◽  
Limbic Thalamus ◽  
Level Function ◽  
Nmdar Subunit ◽  
Circuit Function ◽  
Activity Dependent

AbstractDepression is a pervasive and debilitating neuropsychiatric disorder. A single, low dose of the NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant major depressive disorder. Developing mechanistic understanding of how NMDAR antagonism alters synapse and circuit function is pivotal to developing translatable, circuit-based therapies for depression. Here using viral vectors, anatomical tracing, fMRI, and optogenetic-assisted circuit analysis, we assessed the role of the NMDAR subunit GluN2B in regulating cellular, synaptic, and circuit-level function and depression-related behavior. We demonstrate that post-developmental deletion of GluN2B from pyramidal neurons in medial prefrontal cortex enhances action potential output in a synaptic activity-dependent manner. GluN2B deletion dictates functional connectivity between mPFC and limbic thalamus but not ventral hippocampus and elicits antidepressant-like behavior. Our findings demonstrate that postsynaptic GluN2B exerts input-specific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

scholarly journals Arteriole Dilation to Synaptic Activation that is Sub-Threshold to Astrocyte Endfoot Ca2+ Transients

2015 ◽  
Vol 35 (9) ◽  
pp. 1411-1415 ◽  
Author(s):  
Ádám Institoris ◽  
David George Rosenegger ◽  
Grant Robert Gordon
Keyword(s):  
Synaptic Activity ◽  
Brain Blood Flow ◽  
Synaptic Activation ◽  
Two Photon ◽  
Rat Neocortex ◽  
Two Photon Fluorescence ◽  
Photon Fluorescence ◽  
Activity Dependent ◽  
Local Brain ◽  
Astrocyte Endfeet

Ca2+-dependent pathways in neurons and astrocyte endfeet initiate changes in arteriole diameter to regulate local brain blood flow. Whether there exists a threshold of synaptic activity in which arteriole diameter is controlled independent of astrocyte endfeet Ca2+ remains unclear. We used two-photon fluorescence microscopy to examine synaptically evoked synthetic or genetic Ca2+ indicator signals around penetrating arterioles in acute slices of the rat neocortex. We discovered a threshold below which vasodilation occurred in the absence of endfeet Ca2+ signals but with consistent neuronal Ca2+ transients, suggesting endfoot Ca2+ is not necessary for activity-dependent vasodilation under subtle degrees of brain activation.

scholarly journals Astrocyte Networks and Epilepsy: When Stars Collide

2009 ◽  
Vol 9 (4) ◽  
pp. 113-115 ◽  
Author(s):  
Michael Wong
Keyword(s):  
Synaptic Transmission ◽  
Gap Junctions ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Epileptiform Activity ◽  
Synaptic Activity ◽  
Structural Basis ◽  
Dependent Manner ◽  
Domain Organization ◽  
Activity Dependent

Loss of Astrocytic Domain Organization in the Epileptic Brain. Oberheim NA, Tian GF, Han X, Peng W, Takano T, Ransom B, Nedergaard M. J Neurosci 2008;28(13):3264–3276. Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain. Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission. Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C. Science 2008;322(5907):1551–1555. Astrocytes provide metabolic substrates to neurons in an activity-dependent manner. However, the molecular mechanisms involved in this function, as well as its role in synaptic transmission, remain unclear. Here, we show that the gap-junction subunit proteins connexin 43 and 30 allow intercellular trafficking of glucose and its metabolites through astroglial networks. This trafficking is regulated by glutamatergic synaptic activity mediated by AMPA receptors. In the absence of extracellular glucose, the delivery of glucose or lactate to astrocytes sustains glutamatergic synaptic transmission and epileptiform activity only when they are connected by gap junctions. These results indicate that astroglial gap junctions provide an activity-dependent intercellular pathway for the delivery of energetic metabolites from blood vessels to distal neurons.

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