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ELife Jul 2023Ca/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this...
Ca/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this study, we focused on understanding how interactions between CaMKIIα and the actin-crosslinking protein α-actinin-2 underlie long-lasting changes in dendritic spine architecture. We found that association of the two proteins was unexpectedly elevated within 2 minutes of NMDA receptor stimulation that triggers structural LTP in primary hippocampal neurons. Furthermore, disruption of interactions between the two proteins prevented the accumulation of enlarged mushroom-type dendritic spines following NMDA receptor activation. α-Actinin-2 binds to the regulatory segment of CaMKII. Calorimetry experiments, and a crystal structure of α-actinin-2 EF hands 3 and 4 in complex with the CaMKII regulatory segment, indicate that the regulatory segment of autoinhibited CaMKII is not fully accessible to α-actinin-2. Pull-down experiments show that occupation of the CaMKII substrate-binding groove by GluN2B markedly increases α-actinin-2 access to the CaMKII regulatory segment. Furthermore, in situ labelling experiments are consistent with the notion that recruitment of CaMKII to NMDA receptors contributes to elevated interactions between the kinase and α-actinin-2 during structural LTP. Overall, our study provides new mechanistic insight into the molecular basis of structural LTP and reveals an added layer of sophistication to the function of CaMKII.
Topics: Calcium-Calmodulin-Dependent Protein Kinase Type 2; Actinin; Receptors, N-Methyl-D-Aspartate; Dendritic Spines; Synapses; Long-Term Potentiation
PubMed: 37489746
DOI: 10.7554/eLife.85008 -
Neuroscience Dec 2023Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in...
Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein-protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.
Topics: Humans; Animals; Female; Male; Mice; Infant; Fragile X Mental Retardation Protein; Dendritic Spines; Transcriptome; Autistic Disorder; Sex Characteristics; Autism Spectrum Disorder; Mice, Knockout; Mutation; Fragile X Syndrome; Disease Models, Animal
PubMed: 37852411
DOI: 10.1016/j.neuroscience.2023.10.001 -
BioRxiv : the Preprint Server For... Sep 2023Neuronal connectivity is regulated during normal brain development with the arrangement of spines and synapses being dependent on the morphology of dendrites. Further,...
Neuronal connectivity is regulated during normal brain development with the arrangement of spines and synapses being dependent on the morphology of dendrites. Further, in multiple neurodevelopmental and aging disorders, disruptions of dendrite formation or shaping is associated with atypical neuronal connectivity. We showed previously that Pdlim5 binds delta-catenin and promotes dendrite branching (Baumert et al., J Cell Biol 2020). We report here that Pdlim5 interacts with PalmD, a protein previously suggested by others to interact with the cytoskeleton (e.g., via adducin/ spectrin) and to regulate membrane shaping. Functionally, the knockdown of PalmD or Pdlim5 in rat primary hippocampal neurons dramatically reduces branching and conversely, PalmD exogenous expression promotes dendrite branching as does Pdlim5. Further, we show that effects of each protein are dependent on the presence of the other. In summary, using primary rat hippocampal neurons we reveal the contributions of a novel Pdlim5:PalmD protein complex, composed of functionally inter-dependent components responsible for shaping neuronal dendrites.
PubMed: 37662414
DOI: 10.1101/2023.08.22.553334 -
Current Opinion in Neurobiology Dec 2023If the genome defines the program for the operations of a cell, signaling networks execute it. These cascades of chemical, cell-biological, structural, and trafficking... (Review)
Review
If the genome defines the program for the operations of a cell, signaling networks execute it. These cascades of chemical, cell-biological, structural, and trafficking events span milliseconds (e.g., synaptic release) to potentially a lifetime (e.g., stabilization of dendritic spines). In principle almost every aspect of neuronal function, particularly at the synapse, depends on signaling. Thus dysfunction of these cascades, whether through mutations, local dysregulation, or infection, leads to disease. The sheer complexity of these pathways is matched by the range of diseases and the diversity of their phenotypes. In this review, we discuss how to build computational models, how these models are essential to tackle this complexity, and the benefits of using families of models at different levels of detail to understand signaling in health and disease.
Topics: Dendritic Spines; Neuronal Plasticity; Signal Transduction; Neurons; Synapses
PubMed: 37972535
DOI: 10.1016/j.conb.2023.102808 -
Science (New York, N.Y.) Jul 2023Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar...
Canonically, each Purkinje cell (PC) in the adult cerebellum receives only one climbing fiber (CF) from the inferior olive. Underlying current theories of cerebellar function is the notion that this highly conserved one-to-one relationship renders Purkinje dendrites into a single computational compartment. However, we discovered that multiple primary dendrites are a near-universal morphological feature in humans. Using tract tracing, immunolabeling, and in vitro electrophysiology, we found that in mice ~25% of mature multibranched cells receive more than one CF input. Two-photon calcium imaging in vivo revealed that separate dendrites can exhibit distinct response properties to sensory stimulation, indicating that some multibranched cells integrate functionally independent CF-receptive fields. These findings indicate that PCs are morphologically and functionally more diverse than previously thought.
Topics: Animals; Humans; Mice; Axons; Dendrites; Purkinje Cells; Synapses
PubMed: 37499000
DOI: 10.1126/science.adi1024 -
Cell Reports Dec 2023Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal...
Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.
Topics: Mice; Animals; Huntington Disease; Neuronal Plasticity; Neurons; Hippocampus; Synapses; Lysosomes; Dendrites; Dendritic Spines
PubMed: 38096054
DOI: 10.1016/j.celrep.2023.113573 -
Nature Communications Jan 2024Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy...
Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.
Topics: Actins; Dendritic Spines; Neuronal Plasticity; Synapses; Mitochondria
PubMed: 38177103
DOI: 10.1038/s41467-023-44233-8 -
The Journal of Biological Chemistry Feb 2024Sterile alpha and toll/interleukin receptor motif-containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD following injury....
Sterile alpha and toll/interleukin receptor motif-containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD following injury. Recent work has defined the mechanisms underlying SARM1's catalytic activity and advanced our understanding of SARM1 function in axons, yet the role of SARM1 signaling in other compartments of neurons is still not well understood. Here, we show in cultured hippocampal neurons that endogenous SARM1 is present in axons, dendrites, and cell bodies and that direct activation of SARM1 by the neurotoxin Vacor causes not just axon degeneration, but degeneration of all neuronal compartments. In contrast to the axon degeneration pathway defined in dorsal root ganglia, SARM1-dependent hippocampal axon degeneration in vitro is not sensitive to inhibition of calpain proteases. Dendrite degeneration downstream of SARM1 in hippocampal neurons is dependent on calpain 2, a calpain protease isotype enriched in dendrites in this cell type. In summary, these data indicate SARM1 plays a critical role in neurodegeneration outside of axons and elucidates divergent pathways leading to degeneration in hippocampal axons and dendrites.
Topics: Animals; Mice; Armadillo Domain Proteins; Axons; Calpain; Cytoskeletal Proteins; Dendrites; Neurons; Signal Transduction
PubMed: 38199568
DOI: 10.1016/j.jbc.2024.105630 -
Scientific Reports Jul 2023In vitro model networks could provide cellular models of physiological relevance to reproduce and investigate the basic function of neural circuits on a chip in the...
In vitro model networks could provide cellular models of physiological relevance to reproduce and investigate the basic function of neural circuits on a chip in the laboratory. Several tools and methods have been developed since the past decade to build neural networks on a chip; among them, microfluidic circuits appear to be a highly promising approach. One of the numerous advantages of this approach is that it preserves stable somatic and axonal compartments over time due to physical barriers that prevent the soma from exploring undesired areas and guide neurites along defined pathways. As a result, neuron compartments can be identified and isolated, and their interconnectivity can be modulated to build a topological neural network (NN). Here, we have assessed the extent to which the confinement imposed by the microfluidic environment can impact cell development and shape NN activity. Toward that aim, microelectrode arrays have enabled the monitoring of the short- and mid-term evolution of neuron activation over the culture period at specific locations in organized (microfluidic) and random (control) networks. In particular, we have assessed the spike and burst rate, as well as the correlations between the extracted spike trains over the first stages of maturation. This study enabled us to observe intense neurite communications that would have been weaker and more delayed within random networks; the spiking rate, burst and correlations being reinforced over time in terms of number and amplitude, exceeding the electrophysiological features of standard cultures. Beyond the enhanced detection efficiency that was expected from the microfluidic channels, the confinement of cells seems to reinforce neural communications and cell development throughout the network.
Topics: Microfluidics; Neurons; Neurites; Axons; Cardiac Electrophysiology
PubMed: 37516789
DOI: 10.1038/s41598-023-39477-9 -
PLoS Computational Biology Jun 2024A fundamental function of cortical circuits is the integration of information from different sources to form a reliable basis for behavior. While animals behave as if...
A fundamental function of cortical circuits is the integration of information from different sources to form a reliable basis for behavior. While animals behave as if they optimally integrate information according to Bayesian probability theory, the implementation of the required computations in the biological substrate remains unclear. We propose a novel, Bayesian view on the dynamics of conductance-based neurons and synapses which suggests that they are naturally equipped to optimally perform information integration. In our approach apical dendrites represent prior expectations over somatic potentials, while basal dendrites represent likelihoods of somatic potentials. These are parametrized by local quantities, the effective reversal potentials and membrane conductances. We formally demonstrate that under these assumptions the somatic compartment naturally computes the corresponding posterior. We derive a gradient-based plasticity rule, allowing neurons to learn desired target distributions and weight synaptic inputs by their relative reliabilities. Our theory explains various experimental findings on the system and single-cell level related to multi-sensory integration, which we illustrate with simulations. Furthermore, we make experimentally testable predictions on Bayesian dendritic integration and synaptic plasticity.
Topics: Bayes Theorem; Dendrites; Models, Neurological; Animals; Neuronal Plasticity; Synapses; Computer Simulation; Cues; Computational Biology; Neurons; Action Potentials
PubMed: 38865345
DOI: 10.1371/journal.pcbi.1012047