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 Neuron-based high-content assay and screen for CNS active mitotherapeutics

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw8702 ◽  
Author(s):  
Boglarka H. Varkuti ◽  
Miklos Kepiro ◽  
Ze Liu ◽  
Kyle Vick ◽  
Yosef Avchalumov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hippocampal Neurons ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Glutamate Toxicity ◽  
Primary Neurons ◽  
Screening Assay ◽  
Dynamics And Function ◽  
Small Molecule Modulators ◽  
And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

scholarly journals Activity-Dependent Regulation of the K/Cl Transporter KCC2 Membrane Diffusion, Clustering, and Function in Hippocampal Neurons

2013 ◽  
Vol 33 (39) ◽  
pp. 15488-15503 ◽  
Author(s):  
Ingrid Chamma ◽  
Martin Heubl ◽  
Quentin Chevy ◽  
Marianne Renner ◽  
Imane Moutkine ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Membrane Diffusion ◽  
And Function ◽  
Activity Dependent

scholarly journals Ps in the (Channel) Pod Are Not Alike …

2007 ◽  
Vol 7 (5) ◽  
pp. 136-137
Author(s):  
Yoav Noam ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Phosphorylation Sites ◽  
Voltage Dependent ◽  
Activity Dependent ◽  
Stimulation Of ◽  
Cultured Hippocampal Neurons

Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

scholarly journals MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

2019 ◽  
Vol 116 (12) ◽  
pp. 5727-5736 ◽  
Author(s):  
Mariline M. Silva ◽  
Beatriz Rodrigues ◽  
Joana Fernandes ◽  
Sandra D. Santos ◽  
Laura Carreto ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Surface Expression ◽  
Receptor Expression ◽  
Synaptic Activity ◽  
Synaptic Scaling ◽  
Posttranscriptional Control ◽  
Direct Target ◽  
Activity Dependent

Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

scholarly journals A microRNA signature of toxic extrasynaptic N-methyl-D-aspartate (NMDA) receptor signaling

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Carlos Bas-Orth ◽  
Mirja Koch ◽  
David Lau ◽  
Bettina Buchthal ◽  
Hilmar Bading
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Gene Transcription ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Synaptic Activity ◽  
Aspartate Receptor ◽  
De Novo Gene ◽  
Bath Application ◽  
Stimulation Of

AbstractThe cellular consequences of N-Methyl-D-Aspartate receptor (NMDAR) stimulation depend on the receptors’ subcellular localization. Synaptic NMDARs promote plasticity and survival whereas extrasynaptic NMDARs mediate excitotoxicity and contribute to cell death in neurodegenerative diseases. The mechanisms that couple activation of extrasynaptic NMDARs to cell death remain incompletely understood. We here show that activation of extrasynaptic NMDARs by bath application of NMDA or L-glutamate leads to the upregulation of a group of 19 microRNAs in cultured mouse hippocampal neurons. In contrast, none of these microRNAs is induced upon stimulation of synaptic activity. Increased microRNA expression depends on the pri-miRNA processing enzyme Drosha, but not on de novo gene transcription. These findings suggest that toxic NMDAR signaling involves changes in the expression levels of particular microRNAs.

scholarly journals Munc13 controls the location and efficiency of dense-core vesicle release in neurons

2012 ◽  
Vol 199 (6) ◽  
pp. 883-891 ◽  
Author(s):  
Rhea van de Bospoort ◽  
Margherita Farina ◽  
Sabine K. Schmitz ◽  
Arthur de Jong ◽  
Heidi de Wit ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Dense Core ◽  
Dense Core Vesicle ◽  
Wild Type ◽  
Vesicle Release ◽  
Prolonged Stimulation ◽  
And Function ◽  
Activity Dependent ◽  
Single Vesicle

Neuronal dense-core vesicles (DCVs) contain diverse cargo crucial for brain development and function, but the mechanisms that control their release are largely unknown. We quantified activity-dependent DCV release in hippocampal neurons at single vesicle resolution. DCVs fused preferentially at synaptic terminals. DCVs also fused at extrasynaptic sites but only after prolonged stimulation. In munc13-1/2–null mutant neurons, synaptic DCV release was reduced but not abolished, and synaptic preference was lost. The remaining fusion required prolonged stimulation, similar to extrasynaptic fusion in wild-type neurons. Conversely, Munc13-1 overexpression (M13OE) promoted extrasynaptic DCV release, also without prolonged stimulation. Thus, Munc13-1/2 facilitate DCV fusion but, unlike for synaptic vesicles, are not essential for DCV release, and M13OE is sufficient to produce efficient DCV release extrasynaptically.

scholarly journals Sensory experience controls dendritic structure and behavior by distinct pathways involving degenerins

2018 ◽  
Author(s):  
Sharon Inberg ◽  
Benjamin Podbilewicz
Keyword(s):  
Behavioral Plasticity ◽  
Dendritic Structure ◽  
Dendritic Tree ◽  
Structure And Function ◽  
Dendritic Morphology ◽  
Epithelial Sodium Channels ◽  
And Function ◽  
And Behavior ◽  
Activity Dependent ◽  
Stimulation Of

AbstractTree-like neurites are crucial for receiving information into neurons. It is assumed that nurturing affects the structure and function of dendrites, yet the evidence is scarce, and the mechanisms are unknown. To study whether mechanosensory experience affects dendritic morphology, we use natural mechanical stimulation of the Caenorhabditis elegans’ polymodal PVD neurons, induced by physical contacts between individuals. We found that animal isolation affects the dendritic tree structure of the PVD. Moreover, developmentally isolated animals show a decrease in their ability to respond to harsh touch. The structural and behavioral plasticity following mechanosensory deprivation are functionally independent of each other and are mediated by an array of evolutionary conserved amiloride-sensitive epithelial sodium channels (degenerins). Our results suggest an activity-dependent homeostatic mechanism for dendritic structural plasticity, acting downstream to mechanosensory activation of degenerins.

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.

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