Structural plasticity of dendritic spines

Dendritic spines are the major targets of excitatory synaptic input. They exist in a wide variety of shapes and sizes, from thin to mushroom-shaped to stubby. One of the striking characteristics of dendritic spines is their motile nature. Spines can undergo various structural modifications such as changes in density, shape, size, and motility. During development, spines are highly dynamic and many spines are formed and eliminated. As animals mature, most spines become stable and the vast majority of them can last throughout life. However, spine morphology can still undergo progressive changes. Structural dynamics of dendritic spines is thought to play important roles in synapse plasticity and information processing. Abnormal spine structures are often associated with malfunction of the nervous system.     

Structural plasticity of dendritic spines: The underlying mechanisms and its dysregulation in brain disorders

Dendritic spines are specialized structures on neuronal processes where the majority of excitatory synapses are localized. Spines are highly dynamic, and their stabilization and morphology are influenced by synaptic activity. This extrinsic regulation of spine morphogenesis underlies experience-dependent brain development and information storage within the brain circuitry. In this review, we summarize recent findings that demonstrate the phenomenon of activity-dependent structural plasticity and the molecular mechanisms by which synaptic activity sculpt neuronal connections. Impaired structural plasticity is associated with perturbed brain function in neurodevelopmental disorders such as autism. Information from the mechanistic studies therefore provides important insights into the design of therapeutic strategies for these brain disorders.     

Structure, development, and plasticity of dendritic spines.

Dendritic spines are distinguished by their shapes, subcellular composition, and synaptic receptor subtypes. Recent studies show that actin-dependent movements take place in spine heads, that spines emerge from stubby and shaft synapses after dendritic filopodia disappear, and that spines can form without synaptic activation, are maintained by optimal activation, and are lost with excessive activation or during degeneration.     

Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines

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Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines

Activity-dependent rapid structural and functional modifications of central excitatory synapses contribute to synapse maturation, experience-dependent plasticity, and learning and memory and are associated with neurodevelopmental and psychiatric disorders. However, the signal transduction mechanisms that link glutamate receptor activation to intracellular effectors that accomplish structural and functional plasticity are not well understood. Here we report that NMDA receptor activation in pyramidal neurons causes CaMKII-dependent phosphorylation of the guanine-nucleotide exchange factor (GEF) kalirin-7 at residue threonine 95, regulating its GEF activity, leading to activation of small GTPase Rac1 and rapid enlargement of existing spines. Kalirin-7 also interacts with AMPA receptors and controls their synaptic expression. By demonstrating that kalirin expression and spine localization are required for activity-dependent spine enlargement and enhancement of AMPAR-mediated synaptic transmission, our study identifies a signaling pathway that controls structural and functional spine plasticity.     

Calcium dynamics in dendritic spines: a link to structural plasticity

Calcium signals evoked either by action potential or by synaptic activity play a crucial role for the synaptic plasticity within an individual spine. Because of the small size of spine and the indicators commonly used to measure spine calcium activity, calcium function can be severely disrupted. Therefore, it is very difficult to explain the exact relationship between spine geometry and spine calcium dynamics. Recently, it has been suggested that the medium range of calcium which induces long term potentiation leads to the structural stability stage of spines, while very low or very high amount of calcium leads to the long term depression stage which results in shortening and eventually pruning of spines. Here we propose a physiologically realistic computational model to examine the role of calcium and the mechanisms that govern its regulation in the spine morphology. Calcium enters into spine head through NMDA and AMPA channels and is regulated by internal stores. Contribution of this calcium in the induction of long term potentiation and long term depression is also discussed. Further it has also been predicted that the presence of internal stores depletes the total calcium accumulation in cytosol which is in agreement with the recent experimental and theoretical studies.     

Role of presenilin 1 in structural plasticity of cortical dendritic spines in vivo

Mutations in presenilins are the major cause of familial Alzheimer's disease (FAD), leading to impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Presenilins are the catalytic subunits of γ-secretase, which itself is critically involved in the processing of amyloid precursor protein to release neurotoxic amyloid β (Aβ). Besides Aβ generation, there is growing evidence that presenilins play an essential role in the formation and maintenance of synapses. To further elucidate the effect of presenilin1 (PS1) on synapses, we performed longitudinal in vivo two-photon imaging of dendritic spines in the somatosensory cortex of transgenic mice over-expressing either human wild-type PS1 or the FAD-mutated variant A246E (FAD-PS1). Interestingly, the consequences of transgene expression were different in two subtypes of cortical dendrites. On apical layer 5 dendrites, we found an enhanced spine density in both mice over-expressing human wild-type presenilin1 and FAD-PS1, whereas on basal layer 3 dendrites only over-expression of FAD-PS1 increased the spine density. Time-lapse imaging revealed no differences in kinetically distinct classes of dendritic spines nor was the shape of spines affected. Although γ-secretase-dependent processing of synapse-relevant proteins seemed to be unaltered, higher expression levels of ryanodine receptors suggest a modified Ca(2+) homeostasis in PS1 over-expressing mice. However, the conditional depletion of PS1 in single cortical neurons had no observable impact on dendritic spines. In consequence, our results favor the view that PS1 influences dendritic spine plasticity in a gain-of-function but γ-secretase-independent manner.     

The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses

The proper intracellular distribution of mitochondria is assumed to be critical for normal physiology of neuronal cells, but direct evidence for this idea is lacking. Extension or movement of mitochondria into dendritic protrusions correlates with the development and morphological plasticity of spines. Molecular manipulations of dynamin-like GTPases Drp1 and OPA1 that reduce dendritic mitochondria content lead to loss of synapses and dendritic spines, whereas increasing dendritic mitochondrial content or mitochondrial activity enhances the number and plasticity of spines and synapses. Thus, the dendritic distribution of mitochondria is essential and limiting for the support of synapses. Reciprocally, synaptic activity modulates the motility and fusion/fission balance of mitochondria and controls mitochondrial distribution in dendrites.     

The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines

Synapse function and plasticity depend on the physical structure of dendritic spines as determined by the actin cytoskeleton. We have investigated the organization of filamentous (F-) actin within individual spines on CA1 pyramidal neurons in rat hippocampal slices. Using two-photon photoactivation of green fluorescent protein fused to beta-actin, we found that a dynamic pool of F-actin at the tip of the spine quickly treadmilled to generate an expansive force. The size of a stable F-actin pool at the base of the spine depended on spine volume. Repeated two-photon uncaging of glutamate formed a third pool of F-actin and enlarged the spine. The spine often released this "enlargement pool" into the dendritic shaft, but the pool had to be physically confined by a spine neck for the enlargement to be long-lasting. Ca2+/calmodulin-dependent protein kinase II regulated this confinement. Thus, spines have an elaborate mechanical nature that is regulated by actin fibers.     

Dendritic spines and long-term plasticity

A recent flurry of time-lapse imaging studies of live neurons have tried to address the century-old question: what morphological changes in dendritic spines can be related to long-term memory? Changes that have been proposed to relate to memory include the formation of new spines, the enlargement of spine heads and the pruning of spines. These observations also relate to a more general question of how stable dendritic spines are. The objective of this review is to critically assess the new data and to propose much needed criteria that relate spines to memory, thereby allowing progress in understanding the morphological basis of memory.     

Electrical advantages of dendritic spines

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations.     

Structural dynamics of dendritic spines: Molecular composition,geometry and functional regulation

The development of dendritic spines with specific geometry and membrane composition is critical for proper synaptic function. Specific spine membrane architecture, sub-spine microdomains and spine head and neck geometry allow for well-coordinated and compartmentalized signaling, disruption of which could lead to various neurological diseases. Research from neuronal cell culture, brain slices and direct in vivo imaging indicates that dendritic spine development is a dynamic process which includes transition from small dendritic filopodia through a series of structural refinements to elaborate spines of various morphologies. Despite intensive research, the precise coordination of this morphological transition, the changes in molecular composition, and the relation of spines of various morphologies to function remain a central enigma in the development of functional neuronal circuits. Here, we review research so far and aim to provide insight into the key events that drive structural change during transition from immature filopodia to fully functional spines and the relevance of spine geometry to function.     

Cytoplasmic organization in cerebellar dendritic spines

Three sets of filamentous structures were found to be associated with synaptic junctions in slices of cerebellar tissue prepared by rapid- freezing and freeze-etch techniques. The electron-dense fuzz subjacent to postsynaptic membranes corresponds to a web of 4-6-nm-diam filaments that were clearly visualized in rapid-frozen, freeze-etched preparations. Purkinje cell dendritic spines are filled with a meshwork of 5-7-nm filaments that were found to contact the spine membrane everywhere except at the synaptic junction, and extend through the neck of the spine into the parent dendrite. In addition, 8-10-nm microfilaments, possibly actin, were seen to be associated with the postsynaptic web and to extend into the body and neck of the spine. The arrangements and attachments of the filamentous elements in the Purkinje cell dendritic spine may account for its shape.     

MARCKS for maintenance in dendritic spines

Synapses in the brain must maintain a balance between learning-related plasticity and the stability necessary for reliable function. In this issue of Neuron, Calabrese and Halpain describe cell-transfection experiments implicating MARCKS, a protein that binds to both the cell surface and actin cytoskeleton, in the maintenance of dendritic spines.     

Time-lapse imaging of dendritic spines in vitro

Dendritic spines are small protrusions present postsynaptically at approximately 90% of excitatory synapses in the brain. Spines undergo rapid spontaneous changes in shape that are thought to be important for alterations in synaptic connectivity underlying learning and memory. Visualization of these dynamic changes in spine morphology are especially challenging because of the small size of spines (approximately 1 microm). Here we describe a microscope system, based on a spinning-disk confocal microscope, suitable for imaging mature dendritic spines in brain slice preparations, with a time resolution of seconds. We discuss two commonly used in vitro brain slice preparations and methods for transfecting them. Preparation and transfection require approximately 1 d, after which slices must be cultured for at least 21 d to obtain spines of mature morphology. We also describe imaging and computer analysis routines for studying spine motility. These procedures require in the order of 2 to 4 h.     

Loss of dendritic spines in Alzheimer's disease

Neurones from five patients with Alzheimer's disease were studied semi-quantitatively on Golgi impregnated samples of cerebral cortex. They showed a dramatic reduction in dendritic spine number of pyramidal and non-pyramidal cells of all neocortical layers, as compared with control samples matched for age. Dendritic spine loss could be an initial phenomenon in Alzheimer's disease pathology.     

Structure and molecular organization of dendritic spines

Dendritic spines mediate most excitatory synapses in the CNS and are therefore likely to be of major importance for neural processing. We review the structural aspects of dendritic spines, with particular emphasis on recent advances in the characterization of their molecular components. Spine morphology is very diverse and spine size is correlated with the strength of the synaptic transmission. In addition, the spine neck biochemically isolates individual synapses. Therefore, spine morphology directly reflects its function. A large number of molecules have been described in spines, involving several biochemical families. Considering the small size of a spine, the variety of molecules found is astounding, suggesting that spines are paramount examples of biological nanotechnology. Single-molecular studies appear necessary for future progress. The purpose of this rich molecular diversity is still mysterious but endows synapses with a diverse and flexible biochemical machinery.     

Spatiotemporal maps of CaMKII in dendritic spines

The calcium calmodulin dependent kinase (CaMKII) is important for long-term potentiation at dendritic spines. Photo-activatable GFP (PaGFP) - CaMKII fusions were used to map CaMKII movements between and within spines in dissociated hippocampal neurons. Photo-activated PaGFP (GFP*) generated in the shaft spread uniformly, but was retained for about 1?s in spines. The differential localization of GFP*-CaMKII isoforms was visualized with hundred nanometer precision frame to frame using de-noising algorithms. GFP*-CaMKIIα localized to the tips of mushroom spines. The spatiotemporal profiles of native and kinase defective GFP*-CaMKIIβ, differed markedly from GFP*-CaMKIIα and mutant GFP*-CaMKIIβ lacking the association domain. CaMKIIβ bound to cortical actin in the dendrite and the stable actin network in spine bodies. Glutamate produced a transiently localized GFP*-CaMKIIα fraction and a soluble GFP*-CaMKIIβ fraction in spine bodies. Single molecule simulations of the interplay between diffusion and biochemistry of GFP* species were guided by the spatiotemporal maps and set limits on binding parameters. They highlighted the role of spine morphology in modulating bound CaMKII lifetimes. The long residence times of GFP*-CaMKIIβ relative to GFP*-CaMKIIα followed as consequence of more binding sites on the actin cytoskeleton than the post-synaptic density. These factors combined to retain CaMKII for tens of seconds, sufficient to outlast the calcium transients triggered by glutamate, without invoking complex biochemistry.     

Dually innervated dendritic spines develop in the absence of excitatory activity and resist plasticity through tonic inhibitory crosstalk

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