-
Seminars in Cell & Developmental Biology May 2022Synapses are specialized sites where neurons connect and communicate with each other. Activity-dependent modification of synaptic structure and function provides a... (Review)
Review
Synapses are specialized sites where neurons connect and communicate with each other. Activity-dependent modification of synaptic structure and function provides a mechanism for learning and memory. The advent of high-resolution time-lapse imaging in conjunction with fluorescent biosensors and actuators enables researchers to monitor and manipulate the structure and function of synapses both in vitro and in vivo. This review focuses on recent imaging studies on the synaptic modification underlying learning and memory.
Topics: Dendritic Spines; Learning; Neurons; Synapses
PubMed: 34020876
DOI: 10.1016/j.semcdb.2021.05.015 -
Advances in Pharmacology (San Diego,... 2021Protein phosphatase-1 (PP-1), a highly conserved multifunctional serine/threonine phosphatase, is enriched in dendritic spines where it plays a major role in modulating... (Review)
Review
Protein phosphatase-1 (PP-1), a highly conserved multifunctional serine/threonine phosphatase, is enriched in dendritic spines where it plays a major role in modulating excitatory synaptic activity. In addition to established functions in spine maturation and development, multi-subunit holoenzyme forms of PP-1 modulate higher-order cognitive functions such learning and memory. Mechanisms involved in regulating PP-1 activity and localization in spines include interactions with neurabin and spinophilin, structurally related synaptic scaffolding proteins associated with the actin cytoskeleton. Since PP-1 is a critical element in synaptic development, signaling, and plasticity, alterations in PP-1 signaling in dendritic spines are implicated in various neurological and psychiatric disorders. The effects of PP-1 depend on its isoform-specific association with regulatory proteins and activation of downstream signaling pathways. Here we review the role of PP-1 and its binding proteins neurabin and spinophilin in both developing and established dendritic spines, as well as some of the disorders that result from its dysregulation.
Topics: Actin Cytoskeleton; Animals; Dendritic Spines; Humans; Models, Biological; Nervous System Diseases; Neuronal Plasticity; Protein Phosphatase 1
PubMed: 33706930
DOI: 10.1016/bs.apha.2020.10.001 -
The Journal of Neuroscience : the... Jan 2022Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum...
Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs. is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1β interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.
Topics: Animals; Autism Spectrum Disorder; COS Cells; Cell Adhesion Molecules; Cells, Cultured; Chlorocebus aethiops; Dendritic Spines; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Somatosensory Cortex
PubMed: 34848499
DOI: 10.1523/JNEUROSCI.1003-21.2021 -
Cells Jul 2021Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family...
Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family with sequence similarity 19 A1 (FAM19A1) is a secreted protein primarily expressed in subsets of terminally differentiated neuronal precursor cells and fully mature neurons in specific brain substructures. Several recent studies have demonstrated the importance of FAM19A1 in brain physiology; however, additional information is needed to support its role in neuronal maturation and function. In this study, dendritic spine morphology in -ablated mice and neurite development during in vitro neurogenesis were examined to understand the putative role of FAM19A1 in neural integrity. Adult -deficient mice showed low dendritic spine density and maturity with reduced dendrite complexity compared to wild-type (WT) littermates. To further explore the effect of FAM19A1 on neuronal maturation, the neurite outgrowth pattern in primary neurons was analyzed in vitro with and without FAM19A1. In response to FAM19A1, WT primary neurons showed reduced neurite complexity, whereas -decifient primary neurons exhibited increased neurite arborization, which was reversed by supplementation with recombinant FAM19A1. Together, these findings suggest that FAM19A1 participates in dendritic spine development and neurite arborization.
Topics: Age Factors; Animals; Brain; Cells, Cultured; Chemokines; Dendritic Spines; Female; Gestational Age; Male; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neuronal Outgrowth; Pregnancy; Signal Transduction; Mice
PubMed: 34440636
DOI: 10.3390/cells10081868 -
Journal of Visualized Experiments : JoVE Sep 2021Dendritic spines are specialized sites of synaptic innervation modulated by activity and serve as substrates for learning and memory. Recently, dendritic spines have...
Dendritic spines are specialized sites of synaptic innervation modulated by activity and serve as substrates for learning and memory. Recently, dendritic spines have been described for DD GABAergic neurons as the input sites from presynaptic cholinergic neurons in the motor circuit of Caenorhabditis elegans. This synaptic circuit can now serve as a powerful new in vivo model of spine morphogenesis and function that exploits the facile genetics and ready accessibility of C. elegans to live-cell imaging. This protocol describes experimental strategies for assessing DD spine structure and function. In this approach, a super-resolution imaging strategy is used to visualize the intricate shapes of actin-rich dendritic spines. To evaluate the DD spine function, the light-activated opsin, Chrimson, stimulates the presynaptic cholinergic neurons, and the calcium indicator, GCaMP, reports the evoked calcium transients in postsynaptic DD spines. Together, these methods comprise powerful approaches for identifying genetic determinants of dendritic spines in C. elegans that could also direct spine morphogenesis and function in the brain.
Topics: Actins; Animals; Caenorhabditis elegans; Dendritic Spines; Diagnostic Imaging; Diagnostic Tests, Routine
PubMed: 34633371
DOI: 10.3791/62676 -
Biomolecules Nov 2021Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined... (Review)
Review
Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from the coalescence of nanodomains. Short-lived domains lasting for a few milliseconds coexist with more stable platforms lasting from minutes to days. This panoply of lateral domains subserves the great variety of demands of cell physiology, particularly high for those implicated in signaling. The dendritic spine, a subcellular structure of neurons at the receiving (postsynaptic) end of central nervous system excitatory synapses, exploits this compartmentalization principle. In its most frequent adult morphology, the mushroom-shaped spine harbors neurotransmitter receptors, enzymes, and scaffolding proteins tightly packed in a volume of a few femtoliters. In addition to constituting a mesoscopic lateral heterogeneity of the dendritic arborization, the dendritic spine postsynaptic membrane is further compartmentalized into spatially delimited nanodomains that execute separate functions in the synapse. This review discusses the functional relevance of compartmentalization and nanodomain organization in synaptic transmission and plasticity and exemplifies the importance of this parcelization in various neurotransmitter signaling systems operating at dendritic spines, using two fast ligand-gated ionotropic receptors, the nicotinic acetylcholine receptor and the glutamatergic receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic examples.
Topics: Dendritic Spines; Neurons; Synapses; Synaptic Transmission
PubMed: 34827695
DOI: 10.3390/biom11111697 -
Cells Feb 2020The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory...
The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.
Topics: Animals; Dendritic Spines; Doublecortin Protein; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Morris Water Maze Test; Transfection
PubMed: 32074971
DOI: 10.3390/cells9020440 -
FASEB Journal : Official Publication of... May 2023Associative learning and memory are fundamental behavioral processes through which organisms adapt to complex environments. Associative memory involves long-lasting... (Review)
Review
Associative learning and memory are fundamental behavioral processes through which organisms adapt to complex environments. Associative memory involves long-lasting changes in synaptic plasticity. Dendritic spines are tiny protrusions from the dendritic shaft of principal neurons, providing the structural basis for synaptic plasticity and brain networks in response to external stimuli. Mounting evidence indicates that dendritic spine dynamics are crucial in different associative memory phases, including acquisition, consolidation, and reconsolidation. Causally bridging dendritic spine dynamics and associative memory is still limited by the suitable tools to measure and control spine dynamics in vivo under behaviorally relevant conditions. Here, we review data providing evidence for the remodeling of dendritic spines during associative memory processing and outline open questions.
Topics: Dendritic Spines; Neuronal Plasticity; Brain; Memory; Neurons; Synapses
PubMed: 37000506
DOI: 10.1096/fj.202202166R -
Seminars in Cell & Developmental Biology May 2023Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size... (Review)
Review
Dendritic spines are small protrusions arising from dendrites and constitute the major compartment of excitatory post-synapses. They change in number, shape, and size throughout life; these changes are thought to be associated with formation and reorganization of neuronal networks underlying learning and memory. As spines in the brain are surrounded by the microenvironment including neighboring cells and the extracellular matrix, their protrusion requires generation of force to push against these structures. In turn, neighboring cells receive force from protruding spines. Recent studies have identified BAR-domain proteins as being involved in membrane deformation to initiate spine formation. In addition, forces for dendritic filopodium extension and activity-induced spine expansion are generated through cooperation between actin polymerization and clutch coupling. On the other hand, force from expanding spines affects neurotransmitter release from presynaptic terminals. Here, we review recent advances in our understanding of the physical aspects of synapse formation and plasticity, mainly focusing on spine dynamics.
Topics: Dendritic Spines; Synaptic Transmission; Neurons; Synapses; Neuronal Plasticity
PubMed: 35659473
DOI: 10.1016/j.semcdb.2022.05.017 -
Biophysical Journal Nov 2023Dendritic spines are small protrusions that mediate most of the excitatory synaptic transmission in the brain. Initially, the anatomical structure of spines has... (Review)
Review
Dendritic spines are small protrusions that mediate most of the excitatory synaptic transmission in the brain. Initially, the anatomical structure of spines has suggested that they serve as isolated biochemical and electrical compartments. Indeed, following ample experimental evidence, it is now widely accepted that a significant physiological role of spines is to provide biochemical compartmentalization in signal integration and plasticity in the nervous system. In contrast to the clear biochemical role of spines, their electrical role is uncertain and is currently being debated. This is mainly because spines are small and not accessible to conventional experimental methods of electrophysiology. Here, I focus on reviewing the literature on the electrical properties of spines, including the initial morphological and theoretical modeling studies, indirect experimental approaches based on measurements of diffusional resistance of the spine neck, indirect experimental methods using two-photon uncaging of glutamate on spine synapses, optical imaging of intracellular calcium concentration changes, and voltage imaging with organic and genetically encoded voltage-sensitive probes. The interpretation of evidence from different preparations obtained with different methods has yet to reach a consensus, with some analyses rejecting and others supporting an electrical role of spines in regulating synaptic signaling. Thus, there is a need for a critical comparison of the advantages and limitations of different methodological approaches. The only experimental study on electrical signaling monitored optically with adequate sensitivity and spatiotemporal resolution using voltage-sensitive dyes concluded that mushroom spines on basal dendrites of cortical pyramidal neurons in brain slices have no electrical role.
Topics: Dendritic Spines; Dendrites; Pyramidal Cells; Synaptic Transmission; Glutamic Acid; Synapses
PubMed: 37837192
DOI: 10.1016/j.bpj.2023.10.008