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PLoS Biology Aug 2023Dendritic spines, the tiny and actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain that control...
Dendritic spines, the tiny and actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain that control synaptic activity and plasticity. Dendritic spines contain a specialized form of endoplasmic reticulum (ER), i.e., the spine apparatus, required for local calcium signaling and that is involved in regulating dendritic spine enlargement and synaptic plasticity. Many autism-linked genes have been shown to play critical roles in synaptic formation and plasticity. Among them, KLHL17 is known to control dendritic spine enlargement during development. As a brain-specific disease-associated gene, KLHL17 is expected to play a critical role in the brain, but it has not yet been well characterized. In this study, we report that KLHL17 expression in mice is strongly regulated by neuronal activity and KLHL17 modulates the synaptic distribution of synaptopodin (SYNPO), a marker of the spine apparatus. Both KLHL17 and SYNPO are F-actin-binding proteins linked to autism. SYNPO is known to maintain the structure of the spine apparatus in mature spines and contributes to synaptic plasticity. Our super-resolution imaging using expansion microscopy demonstrates that SYNPO is indeed embedded into the ER network of dendritic spines and that KLHL17 is closely adjacent to the ER/SYNPO complex. Using mouse genetic models, we further show that Klhl17 haploinsufficiency and knockout result in fewer dendritic spines containing ER clusters and an alteration of calcium events at dendritic spines. Accordingly, activity-dependent dendritic spine enlargement and neuronal activation (reflected by extracellular signal-regulated kinase (ERK) phosphorylation and C-FOS expression) are impaired. In addition, we show that the effect of disrupting the KLHL17 and SYNPO association is similar to the results of Klhl17 haploinsufficiency and knockout, further strengthening the evidence that KLHL17 and SYNPO act together to regulate synaptic plasticity. In conclusion, our findings unravel a role for KLHL17 in controlling synaptic plasticity via its regulation of SYNPO and synaptic ER clustering and imply that impaired synaptic plasticity contributes to the etiology of KLHL17-related disorders.
Topics: Animals; Mice; Actins; Autistic Disorder; Brain; Dendritic Spines; Genes, fos; Hypertrophy; Microfilament Proteins
PubMed: 37651441
DOI: 10.1371/journal.pbio.3002274 -
Ageing Research Reviews Jun 2023Neural circuits, such as synaptic plasticity and neural activity, are critical components of healthy brain function. The consequent dynamic remodeling of neural circuits... (Review)
Review
Neural circuits, such as synaptic plasticity and neural activity, are critical components of healthy brain function. The consequent dynamic remodeling of neural circuits is an ongoing procedure affecting neuronal activities. Disruption of this essential process results in diseases. Advanced microscopic applications such as two-photon laser scanning microscopy have recently been applied to understand neural circuit changes during disease since it can visualize fine structural and functional cellular activation in living animals. In this review, we have summarized the latest work assessing the dynamic rewiring of postsynaptic dendritic spines and modulation of calcium transients in neurons of the intact living brain, focusing on their potential roles in neurological disorders (e.g. Alzheimer's disease, stroke, and epilepsy). Understanding the fine changes that occurred in the brain during disease is crucial for future clinical intervention developments.
Topics: Animals; Humans; Neurons; Neuronal Plasticity; Brain; Alzheimer Disease; Stroke; Dendritic Spines
PubMed: 37061201
DOI: 10.1016/j.arr.2023.101933 -
Advances in Neurobiology 2023Dendritic spines, key sites for neural plasticity, are influenced by gonadal steroids. In this chapter, we review the effects of gonadal steroids on dendritic spine... (Review)
Review
Dendritic spines, key sites for neural plasticity, are influenced by gonadal steroids. In this chapter, we review the effects of gonadal steroids on dendritic spine density in areas important to cognitive function, the hippocampus, and prefrontal cortex. Most of these animal model studies investigated the effects of estrogen in females, but we also include more recent data on androgen effects in both males and females. The underlying genomic and non-genomic mechanisms related to gonadal steroid-induced spinogenesis are also reviewed. Subsequently, we discuss possible reasons for the observed sex differences in many neuropsychiatric diseases, which appear to be caused, in part, by aberrant synaptic connections that may involve dendritic spine pathology. Overall, knowledge concerning the regulation of dendritic spines by gonadal hormones has grown since the initial discoveries in the 1990s, and current research points to a potential role for aberrant spine functioning in many neuropsychiatric disorders.
Topics: Female; Male; Animals; Dendritic Spines; Steroids; Cognition; Genomics; Hormones
PubMed: 37962800
DOI: 10.1007/978-3-031-36159-3_8 -
Experimental Neurology Jun 2024Dendritic spines play a pivotal role in synaptic communication and are crucial for learning and memory processes. Abnormalities in spine morphology and plasticity are...
Dendritic spines play a pivotal role in synaptic communication and are crucial for learning and memory processes. Abnormalities in spine morphology and plasticity are observed in neurodevelopmental and neuropsychiatric disorders, yet the underlying signaling mechanisms remain poorly understood. The microtubule affinity regulating kinase 1 (MARK1) has been implicated in neurodevelopmental disorders, and the MARK1 gene shows accelerated evolution in the human lineage suggesting a role in cognition. However, the in vivo role of MARK1 in synaptogenesis and cognitive functions remains unknown. Here we show that forebrain-specific conditional knockout (cKO) of Mark1 in mice causes defects in dendritic spine morphogenesis in hippocampal CA1 pyramidal neurons with a significant reduction in spine density. In addition, we found loss of MARK1 causes synaptic accumulation of GKAP and GluA2. Furthermore, we found that MARK1 cKO mice show defects in spatial learning in the Morris water maze and reduced anxiety-like behaviors in the elevated plus maze. Taken together, our data show a novel role for MARK1 in regulating dendritic spine morphogenesis and cognitive functions in vivo.
Topics: Animals; Male; Mice; CA1 Region, Hippocampal; Cognition; Dendritic Spines; Maze Learning; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Protein Serine-Threonine Kinases; Pyramidal Cells
PubMed: 38484863
DOI: 10.1016/j.expneurol.2024.114752 -
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 -
Biological Research May 2023Previous studies have shown that peripheral nerve injury can lead to abnormal dendritic spine remodeling in spinal dorsal horn neurons. Inhibition of abnormal dendritic...
Previous studies have shown that peripheral nerve injury can lead to abnormal dendritic spine remodeling in spinal dorsal horn neurons. Inhibition of abnormal dendritic spine remodeling can relieve neuropathic pain. Electroacupuncture (EA) has a beneficial effect on the treatment of neuropathic pain, but the specific mechanism remains unclear. Evidence has shown that slit-robo GTPase activating protein 3 (srGAP3) and Rho GTPase (Rac1) play very important roles in dendritic spine remodeling. Here, we used srGAP3 siRNA and Rac1 activator CN04 to confirm the relationship between SrGAP3 and Rac1 and their roles in improving neuropathic pain with EA. Spinal nerve ligation (SNL) was used as the experimental model, and thermal withdrawal latency (TWL), mechanical withdrawal threshold (MWT), Western blotting, immunohistochemistry and Golgi-Cox staining were used to examine changes in behavioral performance, protein expression and dendritic spines. More dendritic spines and higher expression levels of srGAP3 were found in the initial phase of neuropathic pain. During the maintenance phase, dendritic spines were more mature, which was consistent with lower expression levels of srGAP3 and higher expression levels of Rac1-GTP. EA during the maintenance phase reduced the density and maturity of dendritic spines of rats with SNL, increased the levels of srGAP3 and reduced the levels of Rac1-GTP, while srGAP3 siRNA and CN04 reversed the therapeutic effects of EA. These results suggest that dendritic spines have different manifestations in different stages of neuropathic pain and that EA may inhibit the abnormal dendritic spine remodeling by regulating the srGAP3/Rac1 signaling pathway to alleviate neuropathic pain.
Topics: Animals; Rats; Dendritic Spines; Electroacupuncture; GTP Phosphohydrolases; Guanosine Triphosphate; Neuralgia; rac1 GTP-Binding Protein; Rats, Sprague-Dawley; Signal Transduction; Spinal Nerves
PubMed: 37211600
DOI: 10.1186/s40659-023-00439-0 -
ELife Dec 2020Previously, we showed that cryo fixation of adult mouse brain tissue gave a truer representation of brain ultrastructure in comparison with a standard chemical fixation... (Comparative Study)
Comparative Study
Previously, we showed that cryo fixation of adult mouse brain tissue gave a truer representation of brain ultrastructure in comparison with a standard chemical fixation method (Korogod et al., 2015). Extracellular space matched physiological measurements, there were larger numbers of docked vesicles and less glial coverage of synapses and blood capillaries. Here, using the same preservation approaches, we compared the morphology of dendritic spines. We show that the length of the spine and the volume of its head is unchanged; however, the spine neck width is thinner by more than 30% after cryo fixation. In addition, the weak correlation between spine neck width and head volume seen after chemical fixation was not present in cryo-fixed spines. Our data suggest that spine neck geometry is independent of the spine head volume, with cryo fixation showing enhanced spine head compartmentalization and a higher predicted electrical resistance between spine head and parent dendrite.
Topics: Animals; Artifacts; Brain; Cryopreservation; Dendritic Spines; Fixatives; Male; Mice; Mice, Inbred C57BL; Tissue Fixation
PubMed: 33274717
DOI: 10.7554/eLife.56384 -
International Journal of Molecular... Apr 2021Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry... (Review)
Review
Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.
Topics: Actin Cytoskeleton; Animals; Brain Diseases; Dendritic Spines; Disease Models, Animal; Neuronal Plasticity; Synaptic Transmission
PubMed: 33919977
DOI: 10.3390/ijms22084053 -
The Journal of Neuroscience : the... Feb 2023Memory formation and maintenance is a dynamic process involving the modulation of the actin cytoskeleton at synapses. Understanding the signaling pathways that...
Memory formation and maintenance is a dynamic process involving the modulation of the actin cytoskeleton at synapses. Understanding the signaling pathways that contribute to actin modulation is important for our understanding of synapse formation and function, as well as learning and memory. Here, we focused on the importance of the actin regulator, noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1), in hippocampal dependent behaviors and development. We report that male mice lacking NCK1 have impairments in both short-term and working memory, as well as spatial learning. Additionally, we report sex differences in memory impairment showing that female mice deficient in NCK1 fail at reversal learning in a spatial learning task. We find that NCK1 is expressed in postmitotic neurons but is dispensable for neuronal proliferation and migration in the developing hippocampus. Morphologically, NCK1 is not necessary for overall neuronal dendrite development. However, neurons lacking NCK1 have lower dendritic spine and synapse densities and EM analysis reveal increased postsynaptic density (PSD) thickness in the hippocampal CA1 region of NCK1-deficient mice. Mechanistically, we find the turnover of actin-filaments in dendritic spines is accelerated in neurons that lack NCK1. Together, these findings suggest that NCK1 contributes to hippocampal-dependent memory by stabilizing actin dynamics and dendritic spine formation. Understanding the molecular signaling pathways that contribute to memory formation, maintenance, and elimination will lead to a better understanding of the genetic influences on cognition and cognitive disorders and will direct future therapeutics. Here, we report that the noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) adaptor protein modulates actin-filament turnover in hippocampal dendritic spines. Mice lacking NCK1 show sex-dependent deficits in hippocampal memory formation tasks, have altered postsynaptic densities, and reduced synaptic density. Together, our work implicates NCK1 in the regulation of actin cytoskeleton dynamics and normal synapse development which is essential for memory formation.
Topics: Animals; Female; Male; Mice; Actins; Dendritic Spines; Hippocampus; Neurons; Protein-Tyrosine Kinases; Synapses; Memory
PubMed: 36535770
DOI: 10.1523/JNEUROSCI.0495-21.2022 -
Cytoskeleton (Hoboken, N.J.) Mar 2020The ability of neurons to communicate and store information depends on the activity of synapses which can be located on small protrusions (dendritic spines) or directly... (Review)
Review
The ability of neurons to communicate and store information depends on the activity of synapses which can be located on small protrusions (dendritic spines) or directly on the dendritic shaft. The formation, plasticity, and stability of synapses are regulated by the neuronal cytoskeleton. Actin filaments together with microtubules, neurofilaments, septins, and scaffolding proteins orchestrate the structural organization of both shaft and spine synapses, enabling their efficacy in response to synaptic activation. Synapses critically depend on several factors, which are also mediated by the cytoskeleton, including transport and delivery of proteins from the soma, protein synthesis, as well as surface diffusion of membrane proteins. In this minireview, we focus on recent progress made in the field of cytoskeletal elements of the postsynapse and discuss the differences and similarities between synapses located in the spines versus dendritic shaft.
Topics: Cytoskeleton; Dendritic Spines; Humans; Neurons; Synapses
PubMed: 31762205
DOI: 10.1002/cm.21583