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Neuroscience May 2022Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that...
Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that needs to be controlled for dendrite caliber and resource delivery based on microtubule number. The strength of this relationship varies across dendritic arbors, as illustrated for area CA1 and dentate gyrus. In both regions, proximal dendrites had more microtubules than distal dendrites. For CA1 pyramidal cells, spine density was greater on thicker than thinner dendrites in stratum radiatum, or on the more uniformly thin terminal dendrites in stratum lacunosum moleculare. In contrast, spine density was constant across the cone shaped arbor of tapering dendrites from dentate granule cells. These differences suggest that thicker dendrites supply microtubules to subsequent dendritic branches and local dendritic spines, whereas microtubules in thinner dendrites need only provide resources to local spines. Most microtubules ran parallel to dendrite length and associated with long, presumably stable mitochondria, which occasionally branched into lateral dendritic branches. Short, presumably mobile, mitochondria were tethered to microtubules that bent and appeared to direct them into a thin lateral branch. Prior work showed that dendritic segments with the same number of microtubules had elevated resources in subregions of their dendritic shafts where spine synapses had enlarged, and spine clusters had formed. Thus, additional microtubules were not required for redistribution of resources locally to growing spines or synapses. These results provide new understanding about the potential for microtubules to regulate resource delivery to and from dendritic branches and locally among dendritic spines.
Topics: Animals; Dendrites; Dendritic Spines; Hippocampus; Microtubules; Pyramidal Cells; Rats; Synapses
PubMed: 35218884
DOI: 10.1016/j.neuroscience.2022.02.021 -
Neuroscience Bulletin Nov 2022The back-propagating action potential (bpAP) is crucial for neuronal signal integration and synaptic plasticity in dendritic trees. Its properties (velocity and...
The back-propagating action potential (bpAP) is crucial for neuronal signal integration and synaptic plasticity in dendritic trees. Its properties (velocity and amplitude) can be affected by dendritic morphology. Due to limited spatial resolution, it has been difficult to explore the specific propagation process of bpAPs along dendrites and examine the influence of dendritic morphology, such as the dendrite diameter and branching pattern, using patch-clamp recording. By taking advantage of Optopatch, an all-optical electrophysiological method, we made detailed recordings of the real-time propagation of bpAPs in dendritic trees. We found that the velocity of bpAPs was not uniform in a single dendrite, and the bpAP velocity differed among distinct dendrites of the same neuron. The velocity of a bpAP was positively correlated with the diameter of the dendrite on which it propagated. In addition, when bpAPs passed through a dendritic branch point, their velocity decreased significantly. Similar to velocity, the amplitude of bpAPs was also positively correlated with dendritic diameter, and the attenuation patterns of bpAPs differed among different dendrites. Simulation results from neuron models with different dendritic morphology corresponded well with the experimental results. These findings indicate that the dendritic diameter and branching pattern significantly influence the properties of bpAPs. The diversity among the bpAPs recorded in different neurons was mainly due to differences in dendritic morphology. These results may inspire the construction of neuronal models to predict the propagation of bpAPs in dendrites with enormous variation in morphology, to further illuminate the role of bpAPs in neuronal communication.
Topics: Action Potentials; Dendrites; Neurons; Neuronal Plasticity; Pyramidal Cells
PubMed: 35984622
DOI: 10.1007/s12264-022-00931-9 -
The Journal of Cell Biology Dec 2020Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite...
Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss of function in NDs, the underlying pathogenic mechanisms remain largely unexplored. Here, our search for additional pathogenic contributors to dendrite defects in NDs identifies Relish/NF-κB as a novel gain-of-toxicity-based mediator of dendrite defects in animal models for polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for polyQ diseases, polyQ-induced dendrite defects require Dredd/Caspase-8-mediated endoproteolytic cleavage of Relish to generate the N-terminal fragment, Rel68, and subsequent Charon-mediated nuclear localization of Rel68. Rel68 alone induced neuronal toxicity causing dendrite and behavioral defects, and we identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, we show that Rel68-induced toxicity also contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, our data propose disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.
Topics: Amyotrophic Lateral Sclerosis; Animals; Dendrites; Disease Models, Animal; Drosophila Proteins; Drosophila melanogaster; NF-kappa B
PubMed: 33090185
DOI: 10.1083/jcb.202004107 -
Cerebral Cortex (New York, N.Y. : 1991) Jul 2019Higher brain function relies on proper development of the cerebral cortex, including correct positioning of neurons and dendrite morphology. Disruptions in these...
Higher brain function relies on proper development of the cerebral cortex, including correct positioning of neurons and dendrite morphology. Disruptions in these processes may result in various neurocognitive disorders. Mutations in the CPE gene, which encodes carboxypeptidase E (CPE), have been linked to depression and intellectual disability. However, it remains unclear whether CPE is involved in early brain development and in turn contributes to the pathophysiology of neurocognitive disorders. Here, we investigate the effects of CPE knockdown on early brain development and explore the functional significance of the interaction between CPE and its binding partner p150Glued. We demonstrate that CPE is required for cortical neuron migration and dendrite arborization. Furthermore, we show that expression of CPE-C10 redistributes p150Glued from the centrosome and that disruption of CPE interaction with p150Glued leads to abnormal neuronal migration and dendrite morphology, suggesting that a complex between CPE and p150Glued is necessary for proper neurodevelopment.
Topics: Animals; COS Cells; Carboxypeptidase H; Cell Movement; Cerebral Cortex; Chlorocebus aethiops; Dendrites; Mice; Neurogenesis; Neurons; Rats
PubMed: 29982499
DOI: 10.1093/cercor/bhy155 -
Neuron May 2022Cortical pyramidal neurons receive thousands of synaptic inputs and transform these into action potential output. In this issue of Neuron, Lafourcade et al. (2022)...
Cortical pyramidal neurons receive thousands of synaptic inputs and transform these into action potential output. In this issue of Neuron, Lafourcade et al. (2022) demonstrate that distinct long-range projections to retrosplenial cortex pyramidal neurons are coupled to diverse modes of dendritic integration.
Topics: Action Potentials; Axons; Dendrites; Neurons; Pyramidal Cells
PubMed: 35512635
DOI: 10.1016/j.neuron.2022.04.014 -
Molecular Biology of the Cell Sep 2020Kinetochores connect centromeric chromatin to spindle microtubules during mitosis. Neurons are postmitotic, so it was surprising to identify transcripts of structural...
Kinetochores connect centromeric chromatin to spindle microtubules during mitosis. Neurons are postmitotic, so it was surprising to identify transcripts of structural kinetochore (KT) proteins and regulatory chromosome passenger complex (CPC) and spindle assembly checkpoint (SAC) proteins in neurons after dendrite injury. To test whether these proteins function during dendrite regeneration, postmitotic RNA interference (RNAi) was performed and dendrites or axons were removed using laser microsurgery. Reduction of KT, CPC, and SAC proteins decreased dendrite regeneration without affecting axon regeneration. To understand whether neuronal functions of these proteins rely on microtubules, we analyzed microtubule behavior in uninjured neurons. The number of growing plus, but not minus, ends increased in dendrites with reduced KT, CPC, and SAC proteins, while axonal microtubules were unaffected. Increased dendritic microtubule dynamics was independent of dual leucine zipper kinase (DLK)-mediated stress but was rescued by concurrent reduction of γ-tubulin, the core microtubule nucleation protein. Reduction of γ-tubulin also rescued dendrite regeneration in backgrounds containing kinetochore RNAi transgenes. We conclude that kinetochore proteins function postmitotically in neurons to suppress dendritic microtubule dynamics by inhibiting nucleation.
Topics: Animals; Dendrites; Drosophila; Drosophila Proteins; Gene Expression Regulation; Kinetochores; Microtubule-Associated Proteins; Microtubules; Nerve Regeneration; Nerve Tissue Proteins; Neurons; Spindle Apparatus; Tubulin
PubMed: 32673176
DOI: 10.1091/mbc.E20-04-0237-T -
Current Biology : CB Feb 2021Dendrite morphology is necessary for the correct integration of inputs that neurons receive. The branching mechanisms allowing neurons to acquire their type-specific...
Dendrite morphology is necessary for the correct integration of inputs that neurons receive. The branching mechanisms allowing neurons to acquire their type-specific morphology remain unclear. Classically, axon and dendrite patterns were shown to be guided by molecules, providing deterministic cues. However, the extent to which deterministic and stochastic mechanisms, based upon purely statistical bias, contribute to the emergence of dendrite shape is largely unknown. We address this issue using the Drosophila class I vpda multi-dendritic neurons. Detailed quantitative analysis of vpda dendrite morphogenesis indicates that the primary branch grows very robustly in a fixed direction, though secondary branch numbers and lengths showed fluctuations characteristic of stochastic systems. Live-tracking dendrites and computational modeling revealed how neuron shape emerges from few local statistical parameters of branch dynamics. We report key opposing aspects of how tree architecture feedbacks on the local probability of branch shrinkage. Child branches promote stabilization of parent branches, although self-repulsion promotes shrinkage. Finally, we show that self-repulsion, mediated by the adhesion molecule Dscam1, indirectly patterns the growth of secondary branches by spatially restricting their direction of stable growth perpendicular to the primary branch. Thus, the stochastic nature of secondary branch dynamics and the existence of geometric feedback emphasize the importance of self-organization in neuronal dendrite morphogenesis.
Topics: Animals; Dendrites; Drosophila; Drosophila Proteins; Morphogenesis; Sensory Receptor Cells
PubMed: 33212017
DOI: 10.1016/j.cub.2020.10.054 -
Brain : a Journal of Neurology Jul 2018Dendrite pathology and synapse disassembly are critical features of chronic neurodegenerative diseases. In spite of this, the capacity of injured neurons to regenerate...
Dendrite pathology and synapse disassembly are critical features of chronic neurodegenerative diseases. In spite of this, the capacity of injured neurons to regenerate dendrites has been largely ignored. Here, we show that, upon axonal injury, retinal ganglion cells undergo rapid dendritic retraction and massive synapse loss that preceded neuronal death. Human recombinant insulin, administered as eye drops or systemically after dendritic arbour shrinkage and prior to cell loss, promoted robust regeneration of dendrites and successful reconnection with presynaptic targets. Insulin-mediated regeneration of excitatory postsynaptic sites on retinal ganglion cell dendritic processes increased neuronal survival and rescued light-triggered retinal responses. Further, we show that axotomy-induced dendrite retraction triggered substantial loss of the mammalian target of rapamycin (mTOR) activity exclusively in retinal ganglion cells, and that insulin fully reversed this response. Targeted loss-of-function experiments revealed that insulin-dependent activation of mTOR complex 1 (mTORC1) is required for new dendritic branching to restore arbour complexity, while complex 2 (mTORC2) drives dendritic process extension thus re-establishing field area. Our findings demonstrate that neurons in the mammalian central nervous system have the intrinsic capacity to regenerate dendrites and synapses after injury, and provide a strong rationale for the use of insulin and/or its analogues as pro-regenerative therapeutics for intractable neurodegenerative diseases including glaucoma.
Topics: Animals; Axons; Central Nervous System; Dendrites; Glaucoma; Insulin; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Nerve Regeneration; Optic Nerve; Optic Nerve Injuries; Retina; Retinal Ganglion Cells; Signal Transduction; Synapses; TOR Serine-Threonine Kinases
PubMed: 29931057
DOI: 10.1093/brain/awy142 -
PLoS Biology Nov 2022The neuronal microtubule cytoskeleton is key to establish axon-dendrite polarity. Dendrites are characterized by the presence of minus-end out microtubules. However, the...
The neuronal microtubule cytoskeleton is key to establish axon-dendrite polarity. Dendrites are characterized by the presence of minus-end out microtubules. However, the mechanisms that organize these microtubules with the correct orientation are still poorly understood. Using Caenorhabditis elegans as a model system for microtubule organization, we characterized the role of 2 microtubule minus-end related proteins in this process, the microtubule minus-end stabilizing protein calmodulin-regulated spectrin-associated protein (CAMSAP/PTRN-1), and the NINEIN homologue, NOCA-2 (noncentrosomal microtubule array). We found that CAMSAP and NINEIN function in parallel to mediate microtubule organization in dendrites. During dendrite outgrowth, RAB-11-positive vesicles localized to the dendrite tip to nucleate microtubules and function as a microtubule organizing center (MTOC). In the absence of either CAMSAP or NINEIN, we observed a low penetrance MTOC vesicles mislocalization to the cell body, and a nearly fully penetrant phenotype in double mutant animals. This suggests that both proteins are important for localizing the MTOC vesicles to the growing dendrite tip to organize microtubules minus-end out. Whereas NINEIN localizes to the MTOC vesicles where it is important for the recruitment of the microtubule nucleator γ-tubulin, CAMSAP localizes around the MTOC vesicles and is cotranslocated forward with the MTOC vesicles upon dendritic growth. Together, these results indicate that microtubule nucleation from the MTOC vesicles and microtubule stabilization are both important to localize the MTOC vesicles distally to organize dendritic microtubules minus-end out.
Topics: Animals; Caenorhabditis elegans; Microtubules; Microtubule-Organizing Center; Tubulin; Dendrites; Microtubule-Associated Proteins; Caenorhabditis elegans Proteins
PubMed: 36395330
DOI: 10.1371/journal.pbio.3001855 -
Journal of Cell Science Jun 2015The microtubule-based molecular motor dynein is essential for proper neuronal morphogenesis. Dynein activity is regulated by cofactors, and the role(s) of these...
The microtubule-based molecular motor dynein is essential for proper neuronal morphogenesis. Dynein activity is regulated by cofactors, and the role(s) of these cofactors in shaping neuronal structure are still being elucidated. Using Drosophila melanogaster, we reveal that the loss of the dynein cofactor NudE results in abnormal dendrite arborization. Our data show that NudE associates with Golgi outposts, which mediate dendrite branching, suggesting that NudE normally influences dendrite patterning by regulating Golgi outpost transport. Neurons lacking NudE also have increased microtubule dynamics, reflecting a change in microtubule stability that is likely to also contribute to abnormal dendrite growth and branching. These defects in dendritogenesis are rescued by elevating levels of Lis1, another dynein cofactor that interacts with NudE as part of a tripartite complex. Our data further show that the NudE C-terminus is dispensable for dendrite morphogenesis and is likely to modulate NudE activity. We propose that a key function of NudE is to enhance an interaction between Lis1 and dynein that is crucial for motor activity and dendrite architecture.
Topics: Animals; Animals, Genetically Modified; Carrier Proteins; Dendrites; Drosophila Proteins; Drosophila melanogaster; Dyneins; Golgi Apparatus; Microtubule-Associated Proteins; Microtubules
PubMed: 25908857
DOI: 10.1242/jcs.170316