Dendritic spines and distributed circuits

Dendritic spines receive most excitatory connections in pyramidal cells and many other principal neurons. But why do neurons use spines, when they could accommodate excitatory contacts directly on their dendritic shafts? One suggestion is that spines serve to connect with passing axons, thus increasing the connectivity of the dendrites. Another hypothesis is that spines are biochemical compartments that enable input-specific synaptic plasticity. A third possibility is that spines have an electrical role, filtering synaptic potentials and electrically isolating inputs from each other. In this review, I argue that, when viewed from the perspective of the circuit function, these three functions dovetail with one another to achieve a single overarching goal: to implement a distributed circuit with widespread connectivity. Spines would endow these circuits with nonsaturating, linear integration and input-specific learning rules, which would enable them to function as neural networks, with emergent encoding and processing of information.     

Dendritic spines and linear networks

The function of the cortical microcircuitry is still mysterious. Using a bottom-up analysis based on the biophysics and connectivity of cortical neurons, we propose the hypothesis that the neocortex is essentially a linear integrator of inputs. Dendritic spines would slow the neuron and contribute to linearize input summation. Since excitatory axons are relatively straight, they appeared designed to help disperse information to a large number of recipient neurons, generating a distributed circuit. A linear summation regime will ensure the full benefit of a distributed connectivity matrix. Linear integration could also help the neocortex decode the sensory world and may have additional computational advantages. In this view, spines would be the anatomical signature of linear networks.     

Structural plasticity of dendritic spines

Dendritic spines are small mushroom-like protrusions arising from neurons where most excitatory synapses reside. Their peculiar shape suggests that spines can serve as an autonomous postsynaptic compartment that isolates chemical and electrical signaling. How neuronal activity modifies the morphology of the spine and how these modifications affect synaptic transmission and plasticity are intriguing issues. Indeed, the induction of long-term potentiation (LTP) or depression (LTD) is associated with the enlargement or shrinkage of the spine, respectively. This structural plasticity is mainly controlled by actin filaments, the principal cytoskeletal component of the spine. Here we review the pioneering microscopic studies examining the structural plasticity of spines and propose how changes in actin treadmilling might regulate spine morphology.     

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.     

Dendritic spines shaped by synaptic activity

A recent series of exciting observations, using novel high-resolution time-lapse imaging of living cells, has provoked a major shift in our understanding of the dendritic spine, from a stable storage site of long-term memory to a dynamic structure that undergoes rapid morphological variations. Through these recent observations, the molecular mechanisms underlying spine plasticity are beginning to emerge. A common mechanism involving changes in intracellular Ca(2+) concentration may control both the formation/elongation and the pruning/retraction of spines. Spine motility may be instrumental in the formation of synapses, may contribute to the anchoring/removing of glutamate receptors at spine heads, and may control the efficacy of existing synapses.     

Dendritic structural plasticity

Dendrites represent the compartment of neurons primarily devoted to collecting and computating input. Far from being static structures, dendrites are highly dynamic during development and appear to be capable of plastic changes during the adult life of animals. During development, it is a combination of intrinsic programs and external signals that shapes dendrite morphology; input activity is a conserved extrinsic factor involved in this process. In adult life, dendrites respond with more modest modifications of their structure to various types of extrinsic information, including alterations of input activity. Here, the author reviews classical and recent evidence of dendrite plasticity in invertebrates and vertebrates and current progress in the understanding of the molecular mechanisms that underlie this plasticity. Importantly, some fundamental questions such as the functional role of dendrite remodeling and the causal link between structural modifications of neurons and plastic processes, including learning, are still open.     

Dendritic spine morphogenesis and plasticity

Dendritic spines are small protrusions off the dendrite that receive excitatory synaptic input. Spines vary in size, likely correlating with the strength of the synapses they form. In the developing brain, spines show highly dynamic behavior thought to facilitate the formation of new synaptic contacts. Recent studies have illuminated the numerous molecules regulating spine development, many of which converge on the regulation of actin filaments. In addition, interactions with glial cells are emerging as important regulators of spine morphology. In many cases, spine morphogenesis, plasticity, and maintenance also depend on synaptic activity, as shown by recent studies demonstrating changes in spine dynamics and maintenance with altered sensory experience.     

Dendritic spines of the medial amygdala: plasticity, density, shape, and subcellular modulation by sex steroids

The medial nucleus of the amygdala (MeA) is a complex component of the "extended amygdala" in rats. Its posterodorsal subnucleus (MePD) has a remarkable expression of gonadal hormone receptors, is sexually dimorphic or affected by sex steroids, and modulates various social behaviors. Dendritic spines show remarkable changes relevant for synaptic strength and plasticity. Adult males have more spines than females, the density of dendritic spines changes in the course of hours to a few days and is lower in proestrous and estrous phases of the ovarian cycle, or is affected by both sex steroid withdrawal and hormonal replacement therapy in the MePD. Males also have more thin spines than mushroom-like or stubby/wide ones. The presence of dendritic fillopodia and axonal protrusions in the MePD neuropil of adult animals reinforces the evidence for local plasticity. Estrogen affects synaptic and cellular growth and neuroprotection in the MeA by regulating the activity of the cyclic AMP response element-binding protein (CREB)-related gene products, brain-derived neurotrophic factor (BDNF), the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and the activity-regulated cytoskeleton-related protein (Arc). These effects on signal transduction cascades can also lead to local protein synthesis and/or rearrangement of the cytoskeleton and subsequent numerical/morphological alterations in dendritic spines. Various working hypotheses are raised from these experimental data and reveal the MePD as a relevant region to study the effects of sex steroids in the rat brain.     

Dendritic spikes and activity-dependent synaptic plasticity

Whereas the regenerative nature of action potential conduction in axons has been known since the late 1940s, neuronal dendrites have been considered as passive cables transferring incoming synaptic activity to the soma. The relatively recent discovery that neuronal dendrites contain active conductances has revolutionized our view of information processing in neurons. In many neuronal cell types, sodium action potentials initiated at the axon initial segment can back-propagate actively into the dendrite thereby serving, for the dendrite, as an indicator of the output activity of the neuron. In addition, the dendrites themselves can initiate action-potential-like regenerative responses, so-called dendritic spikes, that are mediated either by the activation of sodium, calcium, and/or N-methyl-D-aspartate receptor channels. Here, we review the recent experimental and theoretical evidence for a role of regenerative dendritic activity in information processing within neurons and, especially, in activity-dependent synaptic plasticity.     

Dendritic spines of developing rat cortical neurons in culture

The formation of spines and their association with synapses were examined in developing cultured rat cortical neurons using fluorescence labeling techniques. Small protrusions were found on the processes of cultured cortical neurons after seven days in vitro (DIV), and the density of protrusions almost halved during the second week in vitro, after which it remained unchanged throughout the third week in vitro. The proportion of protrusions associated with the accumulation of the presynaptic marker, synaptophysin, increased steadily from <5% at 7 DIV to approximately 50% at 21 DIV. Based on the absence or presence of an enlargement at the end, protrusions on processes were further divided into filopodia and spines, respectively. The percentage of protrusions that were classified as spines increased steadily from approximately 5% at 3-4 DIV to approximately 80% at 18-20 DIV. The percentage of spines associated with synaptophysin accumulation increased gradually as the cortical neurons developed in vitro, reaching a plateau of approximately 40% after two weeks. However, the percentage of filopodia associated with synaptophysin accumulation never exceeded 5% during the first three weeks in vitro. Double-label staining the microfilaments and beta-tubulin or phosphorylated neurofilament H of cultured neurons further revealed many spines without any nearby axon-like processes. These findings suggest that spines are the dominant form of protrusion on the processes of more mature cortical neurons, that spines are the preferential sites where synapses reside, and that maintaining constant contact with axons is not essential for the formation of spines in cultured cortical neurons.     

Dendritic spines: from structure to in vivo function

Dendritic spines arise as small protrusions from the dendritic shaft of various types of neuron and receive inputs from excitatory axons. Ever since dendritic spines were first described in the nineteenth century, questions about their function have spawned many hypotheses. In this review, we introduce understanding of the structural and biochemical properties of dendritic spines with emphasis on components studied with imaging methods. We then explore advances in in vivo imaging methods that are allowing spine activity to be studied in living tissue, from super-resolution techniques to calcium imaging. Finally, we review studies on spine structure and function in vivo. These new results shed light on the development, integration properties and plasticity of spines.     

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.     

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.     

Dendritic protein synthesis, synaptic plasticity, and memory

Considerable evidence suggests that the formation of long-term memories requires a critical period of new protein synthesis. Recently, the notion that some of these newly synthesized proteins originate through local translation in neuronal dendrites has gained some traction. Here, we review the experimental support for this idea and highlight some of the key questions outstanding in this area.     

EphrinB2 and GRIP1 stabilize mushroom spines during denervation-induced homeostatic plasticity

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

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