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Nature Neuroscience May 2024Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to...
Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to monitor how depolarization impacts local dendritic biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increased the translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long-term potentiation, cell signaling and energy metabolism. This activity-dependent translation was accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs were sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.
Topics: Animals; Dendrites; Eukaryotic Initiation Factor-4G; Protein Biosynthesis; Neurons; Open Reading Frames; Rats; Mice; Cells, Cultured; Potassium Chloride
PubMed: 38589584
DOI: 10.1038/s41593-024-01615-5 -
Trends in Cognitive Sciences Jun 2020The first patch-clamp recordings from the dendrites of human neocortical neurons have recently been reported by Beaulieu-Laroche et al. and Gidon et al. These studies...
The first patch-clamp recordings from the dendrites of human neocortical neurons have recently been reported by Beaulieu-Laroche et al. and Gidon et al. These studies have shown that human dendrites are electrically excitable, exhibiting backpropagating action potentials and fast dendritic calcium spikes. This new frontier highlights the potential for interspecies differences in the biophysics of dendritic computation.
Topics: Action Potentials; Dendrites; Humans; Neurons; Patch-Clamp Techniques; Pyramidal Cells
PubMed: 32392467
DOI: 10.1016/j.tics.2020.03.002 -
Progress in Neurobiology Mar 2015It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations... (Review)
Review
It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function.
Topics: Animals; Brain; Dendrites; Homeostasis; Humans; Memory; Neuronal Plasticity; Synapses
PubMed: 25576663
DOI: 10.1016/j.pneurobio.2014.12.002 -
The Journal of Biological Chemistry 2021Proper dendrite morphogenesis and synapse formation are essential for neuronal development and function. Dasm1, a member of the immunoglobulin superfamily, is known to...
Proper dendrite morphogenesis and synapse formation are essential for neuronal development and function. Dasm1, a member of the immunoglobulin superfamily, is known to promote dendrite outgrowth and excitatory synapse maturation in vitro. However, the in vivo function of Dasm1 in neuronal development and the underlying mechanisms are not well understood. To learn more, Dasm1 knockout mice were constructed and employed to confirm that Dasm1 regulates dendrite arborization and spine formation in vivo. We performed a yeast two-hybrid screen using Dasm1, revealing MRCKβ as a putative partner; additional lines of evidence confirmed this interaction and identified cytoplasmic proline-rich region (823-947 aa) of Dasm1 and MRCKβ self-activated kinase domain (CC1, 410-744 aa) as necessary and sufficient for binding. Using co-immunoprecipitation assay, autophosphorylation assay, and BS3 cross-linking assay, we show that Dasm1 binding triggers a change in MRCKβ's conformation and subsequent dimerization, resulting in autophosphorylation and activation. Activated MRCKβ in turn phosphorylates a class 2 regulatory myosin light chain, which leads to enhanced actin rearrangement, causing the dendrite outgrowth and spine formation observed before. Removal of Dasm1 in mice leads to behavioral abnormalities. Together, these results reveal a crucial molecular pathway mediating cell surface and intracellular signaling communication to regulate actin dynamics and neuronal development in the mammalian brain.
Topics: Actins; Animals; Dendrites; Dendritic Spines; Immunoglobulins; Mice; Nerve Tissue Proteins; Protein Binding; Protein Domains
PubMed: 33933448
DOI: 10.1016/j.jbc.2021.100730 -
The Journal of Neuroscience : the... Feb 2021The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction...
The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG granule cell dendrites and synapses develop normally in KO mice, resembling WT mice at postnatal day 21 (P21), but fail to stabilize, leading to dendrite and synapse loss by P42. These results indicate that Tiam1 promotes DG granule cell dendrite and synapse stabilization late in development. Tiam1 loss also increases the survival, but not the production, of adult-born DG granule cells, possibly because of greater circuit integration as a result of decreased competition with mature granule cells for synaptic inputs. Strikingly, both male and female mice lacking Tiam1 exhibit enhanced contextual fear memory and context discrimination. Together, these results suggest that Tiam1 is a key regulator of DG granule cell stabilization and function within hippocampal circuits. Moreover, based on the enhanced memory phenotype of KO mice, Tiam1 may be a potential target for the treatment of disorders involving memory impairments. The dentate gyrus (DG) is important for learning, memory, pattern separation, and spatial navigation, and its dysfunction is associated with neuropsychiatric disorders. However, the molecular mechanisms controlling DG formation and function remain elusive. By characterizing mice lacking the Rac-GEF Tiam1, we demonstrate that Tiam1 promotes the stabilization of DG granule cell dendritic arbors, spines, and synapses, whereas it restricts the survival of adult-born DG granule cells, which compete with mature granule cells for synaptic integration. Notably, mice lacking Tiam1 also exhibit enhanced contextual fear memory and context discrimination. These findings establish Tiam1 as an essential regulator of DG granule cell development, and identify it as a possible therapeutic target for memory enhancement.
Topics: Animals; Dendrites; Dentate Gyrus; Female; Hippocampus; Male; Memory; Mice; Mice, 129 Strain; Mice, Knockout; Mice, Transgenic; Neurogenesis; Organ Culture Techniques; Synapses; T-Lymphoma Invasion and Metastasis-inducing Protein 1
PubMed: 33328293
DOI: 10.1523/JNEUROSCI.3271-17.2020 -
PLoS Genetics Aug 2020To remodel functional neuronal connectivity, neurons often alter dendrite arbors through elimination and subsequent regeneration of dendritic branches. However, the...
To remodel functional neuronal connectivity, neurons often alter dendrite arbors through elimination and subsequent regeneration of dendritic branches. However, the intrinsic mechanisms underlying this developmentally programmed dendrite regeneration and whether it shares common machinery with injury-induced regeneration remain largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons regenerate adult-specific dendrites after eliminating larval dendrites during metamorphosis. Here we show that the microRNA miR-87 is a critical regulator of dendrite regeneration in Drosophila. miR-87 knockout impairs dendrite regeneration after developmentally-programmed pruning, whereas miR-87 overexpression in C4da neurons leads to precocious initiation of dendrite regeneration. Genetic analyses indicate that the transcriptional repressor Tramtrack69 (Ttk69) is a functional target for miR-87-mediated repression as ttk69 expression is increased in miR-87 knockout neurons and reducing ttk69 expression restores dendrite regeneration to mutants lacking miR-87 function. We further show that miR-87 is required for dendrite regeneration after acute injury in the larval stage, providing a mechanistic link between developmentally programmed and injury-induced dendrite regeneration. These findings thus indicate that miR-87 promotes dendrite regrowth during regeneration at least in part through suppressing Ttk69 in Drosophila sensory neurons and suggest that developmental and injury-induced dendrite regeneration share a common intrinsic mechanism to reactivate dendrite growth.
Topics: Animals; Dendrites; Drosophila Proteins; Drosophila melanogaster; Gene Expression Regulation, Developmental; Larva; Metamorphosis, Biological; MicroRNAs; Nerve Regeneration; Repressor Proteins; Sensory Receptor Cells
PubMed: 32764744
DOI: 10.1371/journal.pgen.1008942 -
Cells Oct 2021Neuronal dendrites receive, integrate, and process numerous inputs and therefore serve as the neuron's "antennae". Dendrites display extreme morphological diversity... (Review)
Review
Neuronal dendrites receive, integrate, and process numerous inputs and therefore serve as the neuron's "antennae". Dendrites display extreme morphological diversity across different neuronal classes to match the neuron's specific functional requirements. Understanding how this structural diversity is specified is therefore important for shedding light on information processing in the healthy and diseased nervous system. Popular models for in vivo studies of dendrite differentiation are the four classes of dendritic arborization (c1da-c4da) neurons of larvae with their class-specific dendritic morphologies. Using da neurons, a combination of live-cell imaging and computational approaches have delivered information on the distinct phases and the time course of dendrite development from embryonic stages to the fully developed dendritic tree. With these data, we can start approaching the basic logic behind differential dendrite development. A major role in the definition of neuron-type specific morphologies is played by dynamic actin-rich processes and the regulation of their properties. This review presents the differences in the growth programs leading to morphologically different dendritic trees, with a focus on the key role of actin modulatory proteins. In addition, we summarize requirements and technological progress towards the visualization and manipulation of such actin regulators in vivo.
Topics: Actins; Animals; Cell Differentiation; Dendrites; Drosophila
PubMed: 34685757
DOI: 10.3390/cells10102777 -
Progress in Neurobiology Aug 2024Dendrites are injured in a variety of clinical conditions such as traumatic brain and spinal cord injuries and stroke. How neurons detect injury directly to their...
Dendrites are injured in a variety of clinical conditions such as traumatic brain and spinal cord injuries and stroke. How neurons detect injury directly to their dendrites to initiate a pro-regenerative response has not yet been thoroughly investigated. Calcium plays a critical role in the early stages of axonal injury detection and is also indispensable for regeneration of the severed axon. Here, we report cell and neurite type-specific differences in laser injury-induced elevations of intracellular calcium levels. Using a human KCNJ2 transgene, we demonstrate that hyperpolarizing neurons only at the time of injury dampens dendrite regeneration, suggesting that inhibition of injury-induced membrane depolarization (and thus early calcium influx) plays a role in detecting and responding to dendrite injury. In exploring potential downstream calcium-regulated effectors, we identify L-type voltage-gated calcium channels, inositol triphosphate signaling, and protein kinase D activity as drivers of dendrite regeneration. In conclusion, we demonstrate that dendrite injury-induced calcium elevations play a key role in the regenerative response of dendrites and begin to delineate the molecular mechanisms governing dendrite repair.
Topics: Dendrites; Animals; Calcium; Nerve Regeneration; Humans; Mice; Potassium Channels, Inwardly Rectifying; Mice, Transgenic
PubMed: 38825174
DOI: 10.1016/j.pneurobio.2024.102635 -
Neuroscience May 2022Decades of experimental and theoretical work support a now well-established theory that active dendritic processing contributes to the computational power of individual... (Review)
Review
Decades of experimental and theoretical work support a now well-established theory that active dendritic processing contributes to the computational power of individual neurons. This theory is based on the high degree of electrical compartmentalization observed in the dendrites of single neurons in ex vivo preparations. Compartmentalization allows dendrites to conduct semi-independent operations on their inputs before final integration and output at the axon, producing a "network-in-a-neuron." However, recent in vivo functional imaging experiments in mouse cortex have reported surprisingly little evidence for strong dendritic compartmentalization. In this review, we contextualize these new findings and discuss their impact on the future of the field. Specifically, we consider how highly coordinated, and thus less compartmentalized, activity in soma and dendrites can contribute to cortical computations including nonlinear mixed selectivity, prediction/expectation, multiplexing, and credit assignment.
Topics: Action Potentials; Animals; Dendrites; Mice; Neurons; Pyramidal Cells
PubMed: 34116137
DOI: 10.1016/j.neuroscience.2021.05.038 -
Cell Reports Nov 2019The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find...
The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find that in the retina, starburst amacrine cells (SACs) and rod bipolar cells (RBCs) express the homophilic cell-surface protein AMIGO2. In Amigo2 knockout (KO) mice, SAC and RBC dendrites expand while arbors of other retinal neurons remain stable. SAC dendrites are divided into a central input region and a peripheral output region that provides asymmetric inhibition to direction-selective ganglion cells (DSGCs). Input and output compartments scale precisely with increased arbor size in Amigo2 KO mice, and SAC dendrites maintain asymmetric connectivity with DSGCs. Increased coverage of SAC dendrites is accompanied by increased direction selectivity of DSGCs without changes to other ganglion cells. Our results identify AMIGO2 as a cell-type-specific dendritic scaling factor and link dendrite size and coverage to visual feature detection.
Topics: Action Potentials; Amacrine Cells; Animals; Dendrites; Gene Knockout Techniques; Membrane Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuronal Plasticity; Retina; Retinal Bipolar Cells; Retinal Ganglion Cells; Synapses
PubMed: 31693896
DOI: 10.1016/j.celrep.2019.09.085