Synaptic Competition Research Articles

Synaptic symmetry breaking by spike timing dependent synaptic plasticity

Recent experimental studies have shown that in various brain regions, such as the hippocampus and the neocortex, both the sign and the magnitude of synaptic modification depend on the precise temporal relation of spike timing of two neurons, which is called spike timing dependent synaptic plasticity (STDP). Due to the asymmetry of the critical window of STDP, STDP tends to lead morphologically reciprocal synaptic connections between two neurons into a functionally uni-directional synaptic connection. We study the spontaneous symmetry breaking of bi-directional synaptic connections between two neurons, which leads the synaptic competition in a larger network. We show that STDP is optimized to the symmetry breaking for the experimentally observed time scale range of the critical window. from Seventeenth Annual Computational Neuroscience Meeting: CNS*2008 Portland, OR, USA. 19–24 July 2008

Bilateral Activity-Dependent Interactions in the Developing Corticospinal System

Activity-dependent competition between the corticospinal (CS) systems in each hemisphere drives postnatal development of motor skills and stable CS tract connections with contralateral spinal motor circuits. Unilateral restriction of motor cortex (M1) activity during an early postnatal critical period impairs contralateral visually guided movements later in development and in maturity. Silenced M1 develops aberrant connections with the contralateral spinal cord whereas the initially active M1, in the other hemisphere, develops bilateral connections. In this study, we determined whether the aberrant pattern of CS tract terminations and motor impairments produced by early postnatal M1 activity restriction could be abrogated by reducing activity-dependent synaptic competition from the initially active M1 later in development. We first inactivated M1 unilaterally between postnatal weeks 5-7. We next inactivated M1 on the other side from weeks 7-11 (alternate inactivation), to reduce the competitive advantage that this side may have over the initially inactivated side. Alternate inactivation redirected aberrant contralateral CS tract terminations from the initially silenced M1 to their normal spinal territories and reduced the density of aberrant ipsilateral terminations from the initially active side. Normal movement endpoint control during visually guided locomotion was fully restored. This reorganization of CS terminals reveals an unsuspected late plasticity after the critical period for establishing the pattern of CS terminations in the spinal cord. Our findings show that robust bilateral interactions between the developing CS systems on each side are important for achieving balance between contralateral and ipsilateral CS tract connections and visuomotor control.

Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination

During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40-/- mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40-/- mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain.

Stable Competitive Dynamics Emerge from Multispike Interactions in a Stochastic Model of Spike-Timing-Dependent Plasticity

In earlier work we presented a stochastic model of spike-timing-dependent plasticity (STDP) in which STDP emerges only at the level of temporal or spatial synaptic ensembles. We derived the two-spike interaction function from this model and showed that it exhibits an STDP-like form. Here, we extend this work by examining the general n-spike interaction functions that may be derived from the model. A comparison between the two-spike interaction function and the higher-order interaction functions reveals profound differences. In particular, we show that the two-spike interaction function cannot support stable, competitive synaptic plasticity, such as that seen during neuronal development, without including modifications designed specifically to stabilize its behavior. In contrast, we show that all the higher-order interaction functions exhibit a fixed-point structure consistent with the presence of competitive synaptic dynamics. This difference originates in the unification of our proposed "switch" mechanism for synaptic plasticity, coupling synaptic depression and synaptic potentiation processes together. While three or more spikes are required to probe this coupling, two spikes can never do so. We conclude that this coupling is critical to the presence of competitive dynamics and that multispike interactions are therefore vital to understanding synaptic competition.

Imaging the motility of dendritic protrusions and axon terminals: roles in axon sampling and synaptic competition

Dendritic spines and filopodia display actin-based morphological plasticity. The function of this rapid motility is unknown. Its ubiquitous expression during development has led to the hypothesis that motility plays a role in synaptogenesis. We investigated this by simultaneously imaging presynaptic boutons and dendritic protrusions in acute hippocampal slices from GFP-M transgenic mice loaded with FM 1-43 followed by immunostaining. Postsynaptic motility was inversely correlated with the presence of stable synaptic contacts. Filopodia were highly motile and made transient interactions, whereas spines were less motile and had stable contacts, although they could still move together with a synaptic terminal. "Head morphing" of spines was associated with interactions with more than one presynaptic terminal. Our data indicate that filopodia motility could serve to transiently sample the surrounding neuropil, while the motility of established spines could mediate interactions with two axonal terminals. Spine "morphing" could therefore be the morphological signature for synaptic input competition in central synapses.

Synaptic homeostasis and input selectivity follow from a calcium-dependent plasticity model.

Modifications in the strengths of synapses are thought to underlie memory, learning, and development of cortical circuits. Many cellular mechanisms of synaptic plasticity have been investigated in which differential elevations of postsynaptic calcium concentrations play a key role in determining the direction and magnitude of synaptic changes. We have previously described a model of plasticity that uses calcium currents mediated by N-methyl-D-aspartate receptors as the associative signal for Hebbian learning. However, this model is not completely stable. Here, we propose a mechanism of stabilization through homeostatic regulation of intracellular calcium levels. With this model, synapses are stable and exhibit properties such as those observed in metaplasticity and synaptic scaling. In addition, the model displays synaptic competition, allowing structures to emerge in the synaptic space that reflect the statistical properties of the inputs. Therefore, the combination of a fast calcium-dependent learning and a slow stabilization mechanism can account for both the formation of selective receptive fields and the maintenance of neural circuits in a state of equilibrium.

Neuregulin Inhibits Acetylcholine Receptor Aggregation in Myotubes

The high local concentration of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction results from their aggregation by the agrin/MuSK signaling pathway and their synthetic up-regulation by the neuregulin/ErbB pathway. Here, we show a novel role for the neuregulin/ErbB pathway, the inhibition of AChR aggregation on the muscle surface. Treatment of C2C12 myotubes with the neuregulin epidermal growth factor domain decreased the number of both spontaneous and agrin-induced AChR clusters, in part by increasing the rate of cluster disassembly. Upon cluster disassembly, AChRs were internalized into caveolae (as identified by caveolin-3). Time-lapse microscopy revealed that individual AChR clusters fragmented into puncta, and application of neuregulin accelerated the rate at which AChR clusters decreased in area without affecting the density of AChRs remaining in individual clusters (as measured by the fluorescence intensity/unit area). We propose that this novel action of neuregulin regulates synaptic competition at the developing neuromuscular junction.

Synaptic regulation on various STDP rules

An additive rule of spike-timing-dependent synaptic plasticity (STDP) automatically achieves synaptic competition and activity regulation, where synaptic balance is moderately regulated to control the post synaptic activity (Song et al., Nature Neurosci. 3 (2000) 919). On the other hand, asymmetrically multiplicative STDP rules cannot achieve the synaptic competition nor the synaptic regulation (Rubin et al., Phys. Rev. Lett. 86 (2001) 364; van Rossum et al., J. Neuroscience 20 (2000) 8812). These works suggest that synaptic efficacy dependence in updating rule is relevant for synaptic competition and activity regulation. There is another possible factor relevant for activity regulation. Various types of spike pair-to-pair interactions on STDP have been found (Froemke and Dan, Nature 416 (2002) 433; Sjöström et al., Neuron 32 (2001) 1149). It is not clear what type of rules can achieve activity regulation and how it is related to synaptic competition. Here we demonstrate various types of updating rules and show that symmetry in synaptic efficacy dependence is relevant for activity regulation, and that activity regulation is independent from competition.

Activity-dependent synaptic competition at mammalian neuromuscular junctions.

Synapse elimination is a widespread developmental process in the peripheral and central nervous system that brings about refinement of neural connections through epigenetic mechanisms. Here we describe recent advances concerning the role of the pattern of motoneuronal firing, synchronous or asynchronous, in neuromuscular synapse elimination.

Trans-endocytosis via spinules in adult rat hippocampus.

Locations of a distinctive mode of trans-endocytosis involving dendrites, axons, and glia were quantified through serial section electron microscopy. Short vesicular or long vermiform evaginations emerged from dendrites and axons and were engulfed by presynaptic or neighboring axons, astrocytes, and, surprisingly, a growth cone to form double-membrane structures called spinules. In total, 254 spinules were evaluated in 326 microm(3) of stratum radiatum in area CA1 of mature rat hippocampus. Spinules emerged from spine heads (62%), necks (24%), axons (13%), dendritic shafts (1%), or nonsynaptic protrusions (<1%) and invaginated into axons (approximately 90%), astrocytic processes (approximately 8%), or a growth cone (approximately 1%). Coated pits occurred on the engulfing membrane at the tips of most spinules (69%), and double-membrane structures occurred freely in axonal and astrocytic cytoplasm, suggesting trans-endocytosis. Spinule locations differed among mushroom and thin spines. For mushroom spines, most (84%) of the spinules were engulfed by presynaptic axons, 16% by neighboring axons, and none by astrocytic processes. At thin spines, only 17% of the spinules were engulfed by presynaptic axons, whereas 67% were engulfed by neighboring axons and 14% by astrocytic processes. Spinules engulfed by astrocytic processes support the growing evidence that perisynaptic glia interact directly with synapses at least on thin spines. Spinules with neighboring axons may provide a mechanism for synaptic competition in the mature brain. Trans-endocytosis of spinules by presynaptic axons suggest retrograde signaling or coordinated remodeling of presynaptic and postsynaptic membranes to remove transient perforations and assemble the postsynaptic density of large synapses on mushroom spines.

Synaptic regulation on various STDP rules

An additive rule of spike-timing-dependent synaptic plasticity (STDP) automatically achieves synaptic competition and activity regulation, where synaptic balance is moderately regulated to control the post synaptic activity (Song et al., Nature Neurosci. 3 (2000) 919). On the other hand, asymmetrically multiplicative STDP rules cannot achieve the synaptic competition nor the synaptic regulation (Rubin et al., Phys. Rev. Lett. 86 (2001) 364; van Rossum et al., J. Neuroscience 20 (2000) 8812). These works suggest that synaptic efficacy dependence in updating rule is relevant for synaptic competition and activity regulation. There is another possible factor relevant for activity regulation. Various types of spike pair-to-pair interactions on STDP have been found (Froemke and Dan, Nature 416 (2002) 433; Sjöström et al., Neuron 32 (2001) 1149). It is not clear what type of rules can achieve activity regulation and how it is related to synaptic competition. Here we demonstrate various types of updating rules and show that symmetry in synaptic efficacy dependence is relevant for activity regulation, and that activity regulation is independent from competition.

P/Q-type Ca2+ channel alpha1A regulates synaptic competition on developing cerebellar Purkinje cells.

Synapse formation depends critically on the competition among inputs of multiple sources to individual neurons. Cerebellar Purkinje cells have highly organized synaptic wiring from two distinct sources of excitatory afferents. Single climbing fibers innervate proximal dendrites of Purkinje cells, whereas numerous parallel fibers converge on their distal dendrites. Here, we demonstrate that the P/Q-type Ca2+ channel alpha1A, a major Ca2+ channel subtype in Purkinje cells, is crucial for this organized synapse formation. In the alpha1A knock-out mouse, many ectopic spines were protruded from proximal dendrites and somata of Purkinje cells. Innervation territory of parallel fibers was expanded proximally to innervate the ectopic spines, whereas that of climbing fibers was regressed to the basal portion of proximal dendrites and somata. Furthermore, multiple climbing fibers consisting of a strong climbing fiber and one or a few weaker climbing fibers, persisted in the majority of Purkinje cells and were cowired to the same somata, proximal dendrites, or both. Therefore, the lack of alpha1A results in the persistence of parallel fibers and surplus climbing fibers, which should normally be expelled from the compartment innervated by the main climbing fiber. These results suggest that a P/Q-type Ca2+ channel alpha1A fuels heterosynaptic competition between climbing fibers and parallel fibers and also fuels homosynaptic competition among multiple climbing fibers. This molecular function facilitates the distal extension of climbing fiber innervation along the dendritic tree of the Purkinje cell and also establishes climbing fiber monoinnervation of individual Purkinje cells.

The role of neuronal identity in synaptic competition.

In developing mammalian muscle, axon branches of several motor neurons co-innervate the same muscle fibre. Competition among them results in the strengthening of one and the withdrawal of the rest. It is not known why one particular axon branch survives or why some competitions resolve sooner than others. Here we show that the fate of axonal branches is strictly related to the identity of the axons with which they compete. When two neurons co-innervate multiple target cells, the losing axon branches in each contest belong to the same neuron and are at nearly the same stage of withdrawal. The axonal arbor of one neuron engages in multiple sets of competitions simultaneously. Each set proceeds at a different rate and heads towards a common outcome based on the identity of the competitor. Competitive vigour at each of these sets of local competitions depends on a globally distributed resource: neurons with larger arborizations are at a competitive disadvantage when confronting neurons with smaller arborizations. An accompanying paper tests the idea that the amount of neurotransmitter released is this global resource.

Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition.

Synaptic activity drives synaptic rearrangement in the vertebrate nervous system; indeed, this appears to be a main way in which experience shapes neural connectivity. One rearrangement that occurs in many parts of the nervous system during early postnatal life is a competitive process called 'synapse elimination'. At the neuromuscular junction, where synapse elimination has been analysed in detail, muscle fibres are initially innervated by multiple axons, then all but one are withdrawn and the 'winner' enlarges. In support of the idea that synapse elimination is activity dependent, it is slowed or speeded when total neuromuscular activity is decreased or increased, respectively. However, most hypotheses about synaptic rearrangement postulate that change depends less on total activity than on the relative activity of the competitors. Intuitively, it seems that the input best able to excite its postsynaptic target would be most likely to win the competition, but some theories and results make other predictions. Here we use a genetic method to selectively inhibit neurotransmission from one of two inputs to a single target cell. We show that more powerful inputs are strongly favoured competitors during synapse elimination.

Activity-dependent elimination of neuromuscular synapses.

At developing neuromuscular synapses in vertebrates, different motor axon inputs to muscle fibers compete for maintenance of their synapses. Competition results in progressive changes in synaptic structure and strength that lead to the weakening and loss of some inputs, a process that has been called synapse elimination. At the same time, a single input is strengthened and maintained throughout adult life, consistently recruiting muscle fibers to contract even at rapid firing rates. Work over the last decade has led to an understanding of some of the cell biological mechanisms that underlie competition and how these culminate in synapse elimination. We discuss current ideas about how activity modulates neuromuscular synaptic competition, how competition leads to synapse loss, and how these processes are modulated by cell-cell signaling. A common feature of competition at neuromuscular as well as CNS synapses is that temporally correlated activity seems to slow or prevent competition, while uncorrelated activity seems to trigger or enhance competition. Important questions that remain to be addressed include how patterns of motor neuron activity affect synaptic strength, what is the temporal relationship between changes in synaptic strength and structure, and what cellular signals mediate synapse loss. Answers to these questions will expand our understanding of the mechanisms by which activity edits synaptic structure and function, writing permanent changes in neural circuitry.

A stochastic method to predict the consequence of arbitrary forms of spike-timing-dependent plasticity.

Synapses in various neural preparations exhibit spike-timing-dependent plasticity (STDP) with a variety of learning window functions. The window functions determine the magnitude and the polarity of synaptic change according to the time difference of pre- and postsynaptic spikes. Numerical experiments revealed that STDP learning with a single-exponential window function resulted in a bimodal distribution of synaptic conductances as a consequence of competition between synapses. A slightly modified window function, however, resulted in a unimodal distribution rather than a bimodal distribution. Since various window functions have been observed in neural preparations, we develop a rigorous mathematical method to calculate the conductance distribution for any given window function. Our method is based on the Fokker-Planck equation to determine the conductance distribution and on the Ornstein-Uhlenbeck process to characterize the membrane potential fluctuations. Demonstrating that our method reproduces the known quantitative results of STDP learning, we apply the method to the type of STDP learning found recently in the CA1 region of the rat hippocampus. We find that this learning can result in nearly optimized competition between synapses. Meanwhile, we find that the type of STDP learning found in the cerebellum-like structure of electric fish can result in all-or-none synapses: either all the synaptic conductances are maximized, or none of them becomes significantly large. Our method also determines the window function that optimizes synaptic competition.

In Vivo Time-Lapse Imaging of Synaptic Takeover Associated with Naturally Occurring Synapse Elimination

During development, competition between axons causes permanent removal of synaptic connections, but the dynamics have not been directly observed. Using transgenic mice that express two spectral variants of fluorescent proteins in motor axons, we imaged competing axons at developing neuromuscular junctions in vivo. Typically, one axon withdrew progressively from postsynaptic sites and the competing axon extended axonal processes to occupy those sites. In rare instances when the remaining axon did not reoccupy a site, the postsynaptic receptors rapidly disappeared. Interestingly, the progress and outcome of competition was unpredictable. Moreover, the relative areas occupied by the competitors shifted in favor of one axon and then the other. These results show synaptic competition is not always monotonic and that one axon's contraction in synaptic area is associated with another axon's expansion.

Spike-timing dependent synaptic plasticity: a phenomenological framework.

In this paper a phenomenological model of spike-timing dependent synaptic plasticity (STDP) is developed that is based on a Volterra series-like expansion. Synaptic weight changes as a function of the relative timing of pre- and postsynaptic spikes are described by integral kernels that can easily be inferred from experimental data. The resulting weight dynamics can be stated in terms of statistical properties of pre- and postsynaptic spike trains. Generalizations to neurons that fire two different types of action potentials, such as cerebellar Purkinje cells where synaptic plasticity depends on correlations in two distinct presynaptic fibers, are discussed. We show that synaptic plasticity, together with strictly local bounds for the weights, can result in synaptic competition that is required for any form of pattern formation. This is illustrated by a concrete example where a single neuron equipped with STDP can selectively strengthen those synapses with presynaptic neurons that reliably deliver precisely timed spikes at the expense of other synapses which transmit spikes with a broad temporal distribution. Such a mechanism may be of vital importance for any neuronal system where information is coded in the timing of individual action potentials.

Peripheral influences during development of the CNS

The amount of cortex devoted to the representations of each sensory system varies dramatically between different species of mammal, and these differences usually reflect the species-specific emphasis and elaboration of different sensory organs. Furthermore, the central representations of sensory systems closely preserve details of their associated receptor fields. For example, the pattern of whiskers on the snout of a mouse or a rat is represented first by barrelettes in the brain stem, then by barreloids in the thalamus and finally by barrels in the cortex. And in primates a disproportionately large area of visual cortex is devoted to representing the high density of photoreceptors in the fovea.The developmental specification of cortical areas has a genetic component, although complex interactions with the periphery are also involved. Sensory organs are able to influence the development of their central representations through a variety of mechanisms, including activity-dependent synaptic plasticity and competition for neurotrophic factors. Because information about the density, topographical arrangement and diversity of receptors can be provided online by the periphery, it does not have to be duplicated in the developmental program of the brain. This gives the brain the flexibility to adapt to the body in which it finds itself, allowing variability in the periphery to be accommodated without specific changes to the brain-wiring program.The extent to which the cortex can accommodate changes in the periphery has been demonstrated by recent experiments with North American opossums [1xMassive cross-model cortical plasticity and the emergence of a new cortical area in developmentally blind mammals. Kahn, D.M. and Krubitzer, L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11429–11434Crossref | PubMed | Scopus (79)See all References[1]. A marsupial was chosen because the extended period of extra-uterine development allows direct access to early stages that are intra-uterine in eutherian mammals. Animals were blinded by bilateral enucleation and then allowed to develop to adulthood. Electrophyioslogical and architectonic maps of the cortex revealed marked reorganization of the sensory areas. Primary visual cortex was greatly reduced, whereas the areas of cortex responsive to either somatosensory or auditory stimuli were expanded. In addition, a new cortical field was identified in which cells were responsive to both somatosensory and auditory stimuli. The results show both the dramatic plasticity of the wiring program of the brain and the influence of the sensory periphery on cortical development. They also provide an invaluable hint as to one mechanism by which new cortical areas emerge during evolution.

Perinatal switch from synchronous to asynchronous activity of motoneurons: link with synapse elimination.

Synaptic competition is a basic feature of developing neural connections. To shed light on its dependence on the activity pattern of competing inputs, we investigated in vivo rat motoneuronal firing during late embryonic and early neonatal life, when synapse elimination occurs in muscle. Electromyographic recordings with floating microelectrodes from tibialis anterior and soleus muscles revealed that action potentials of motoneurons belonging to the same pool have high temporal correlation. The very tight linkage, a few tens of milliseconds, corresponds to the narrow time windows of published paradigms of activity-dependent synaptic plasticity. A striking change occurs, however, soon after birth when motoneuronal firing switches to the adult uncorrelated type. The switch precedes the onset of synapse elimination, whose time course was determined with confocal microscopy. Interestingly, the soleus muscle, whose motoneurons switch to desynchronized activity later than those of the tibialis anterior muscle, also exhibits delayed synapse elimination. Our findings support a developmental model in which synchronous activity first favors polyneuronal innervation, whereas an asynchronous one subsequently promotes synapse elimination.