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Nature Apr 2024Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is...
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Topics: Animals; Female; Humans; Male; Mice; Alternative Splicing; Autistic Disorder; Calcium; Calcium Channels, L-Type; Cell Movement; Dendrites; Exons; Long QT Syndrome; Neurons; Oligonucleotides, Antisense; Organoids; Prosencephalon; Syndactyly; Interneurons
PubMed: 38658687
DOI: 10.1038/s41586-024-07310-6 -
Nature Oct 2023The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse... (Comparative Study)
Comparative Study
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.
Topics: Adolescent; Animals; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Mice; Young Adult; Cognition; Dendritic Spines; Gestational Age; Macaca; Neurons; Post-Synaptic Density; Proteomics; Rho Guanine Nucleotide Exchange Factors; Signal Transduction; Species Specificity; Synapses
PubMed: 37704727
DOI: 10.1038/s41586-023-06542-2 -
Molecular Cell Aug 2023For cells to perform their biological functions, they need to adopt specific shapes and form functionally distinct subcellular compartments. This is achieved in part via...
For cells to perform their biological functions, they need to adopt specific shapes and form functionally distinct subcellular compartments. This is achieved in part via an asymmetric distribution of mRNAs within cells. Currently, the main model of mRNA localization involves specific sequences called "zipcodes" that direct mRNAs to their proper locations. However, while thousands of mRNAs localize within cells, only a few zipcodes have been identified, suggesting that additional mechanisms contribute to localization. Here, we assess the role of mRNA stability in localization by combining the isolation of the soma and neurites of mouse primary cortical and mESC-derived neurons, SLAM-seq, mA-RIP-seq, the perturbation of mRNA destabilization mechanisms, and the analysis of multiple mRNA localization datasets. We show that depletion of mRNA destabilization elements, such as mA, AU-rich elements, and suboptimal codons, functions as a mechanism that mediates the localization of mRNAs associated with housekeeping functions to neurites in several types of neurons.
Topics: Animals; Mice; RNA, Messenger; Neurons; Neurites; Codon; RNA Stability
PubMed: 37451262
DOI: 10.1016/j.molcel.2023.06.021 -
Frontiers in Behavioral Neuroscience 2023Accumulating evidence from a wide range of studies, including behavioral, cellular, molecular and computational findings, support a key role of dendrites in the encoding...
Accumulating evidence from a wide range of studies, including behavioral, cellular, molecular and computational findings, support a key role of dendrites in the encoding and recall of new memories. Dendrites can integrate synaptic inputs in non-linear ways, provide the substrate for local protein synthesis and facilitate the orchestration of signaling pathways that regulate local synaptic plasticity. These capabilities allow them to act as a second layer of computation within the neuron and serve as the fundamental unit of plasticity. As such, dendrites are integral parts of the memory engram, namely the physical representation of memories in the brain and are increasingly studied during learning tasks. Here, we review experimental and computational studies that support a novel, dendritic view of the memory engram that is centered on non-linear dendritic branches as elementary memory units. We highlight the potential implications of dendritic engrams for the learning and memory field and discuss future research directions.
PubMed: 37576932
DOI: 10.3389/fnbeh.2023.1212139 -
Genetics Jun 2024Since the days of Ramón y Cajal, the vast diversity of neuronal and particularly dendrite morphology has been used to catalog neurons into different classes. Dendrite... (Review)
Review
Since the days of Ramón y Cajal, the vast diversity of neuronal and particularly dendrite morphology has been used to catalog neurons into different classes. Dendrite morphology varies greatly and reflects the different functions performed by different types of neurons. Significant progress has been made in our understanding of how dendrites form and the molecular factors and forces that shape these often elaborately sculpted structures. Here, we review work in the nematode Caenorhabditis elegans that has shed light on the developmental mechanisms that mediate dendrite morphogenesis with a focus on studies investigating ciliated sensory neurons and the highly elaborated dendritic trees of somatosensory neurons. These studies, which combine time-lapse imaging, genetics, and biochemistry, reveal an intricate network of factors that function both intrinsically in dendrites and extrinsically from surrounding tissues. Therefore, dendrite morphogenesis is the result of multiple tissue interactions, which ultimately determine the shape of dendritic arbors.
Topics: Animals; Caenorhabditis elegans; Dendrites; Morphogenesis; Caenorhabditis elegans Proteins; Sensory Receptor Cells
PubMed: 38785371
DOI: 10.1093/genetics/iyae056 -
The Journal of Neuroscience : the... Oct 2023The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic... (Review)
Review
The loss of excitatory synapses is known to underlie the cognitive deficits in Alzheimer's disease (AD). Although much is known about the mechanisms underlying synaptic loss in AD, how neurons compensate for this loss and whether this provides cognitive benefits remain almost completely unexplored. In this review, we describe two potential compensatory mechanisms implemented following synaptic loss: the enlargement of the surviving neighboring synapses and the regeneration of synapses. Because dendritic spines, the postsynaptic site of excitatory synapses, are easily visualized using light microscopy, we focus on a range of microscopy approaches to monitor synaptic loss and compensation. Here, we stress the importance of longitudinal dendritic spine imaging, as opposed to fixed-tissue imaging, to gain insights into the temporal dynamics of dendritic spine compensation. We believe that understanding the molecular mechanisms behind these and other forms of synaptic compensation and regeneration will be critical for the development of therapeutics aiming at delaying the onset of cognitive deficits in AD.
Topics: Humans; Alzheimer Disease; Synapses; Neuronal Plasticity; Cognition Disorders; Neurons; Dendritic Spines
PubMed: 37821232
DOI: 10.1523/JNEUROSCI.0379-23.2023