Activity-dependent axonal and synaptic plasticity in the cerebellum

The cerebellum is a brain region endowed with a high degree of plasticity also in adulthood. After damage or alteration in the patterns of activity, it is able to undergo remarkable changes in its architecture and to form new connections based upon a process of synaptic reorganization. This review addresses cellular and molecular mechanisms that regulate the competition between two inputs belonging to different neuronal populations in innervating two contiguous but separate domains of the same target cell. The two inputs are the parallel fibers, the axon of the cerebellar granule cells, and the olivocerebellar neurons, that terminate as climbing fibers in the cerebellar cortex. The target is the Purkinje cell characterized by two dendritic domains that are different in size and number of spines, upon which the two afferent inputs impinge. Both inputs express several genes related to plasticity throughout the life span conferring the ability to remodel their synapses. In addition, we provided evidence that climbing fibers and Purkinje cells show remarkable reciprocal trophic interactions that are required for the maintenance of the correct synaptic connectivity. Through their activity, climbing fibers sustain the competition with parallel fibers by displacing this input to the distal territory of the Purkinje cell dendrite. In addition, they operate on the Purkinje cells through AMPA receptor suppressing spines in the territory surrounding their synapses. In this way, climbing fibers are able to optimize spine distribution and functional connectivity.     

Activity maintains structural plasticity of mossy fiber terminals in the hippocampus

Neural activity plays an important role in organizing and optimizing neural circuits during development and in the mature nervous system. However, the cellular events that underlie this process still remain to be fully understood. In this study, we investigated the role of neural activity in regulating the structural plasticity of presynaptic terminals in the hippocampal formation. We designed a virus to drive the Drosophila Allatostatin receptor in individual dentate granule neurons to suppress activity of complex mossy fiber terminals 'on-demand' in organotypic slices and used time-lapse confocal imaging to determine the impact on presynaptic remodeling. We found that activity played an important role in maintaining the structural plasticity of the core region of the mossy fiber terminal (MFT) that synapses onto CA3 pyramidal cell thorny excrescences but was not essential for the motility of terminal filopodial extensions that contact local inhibitory neurons. Short-term suppression of activity did not have an impact on the size of the MFT, however, longer-term suppression reduced the overall size of the MFT. Remarkably, global blockade of activity with tetrodotoxin (TTX) interfered with the ability of single cell activity deprivation to slow down terminal dynamics suggesting that differences in activity levels among neighboring synapses promote synaptic remodeling events. The results from our studies indicate that neural activity plays an important role in maintaining structural plasticity of presynaptic compartments in the central nervous system and provide new insight into the time-frame during which activity can affect the morphology of synaptic connections.     

Distribution and structure of identified tonic and phasic synapses between L-neurones in the locust ocellar tract.

The ultrastructures and distributions of the discrete anatomical synapses which constitute two distinct types of output connections made by individual ocellar L-neurons, L1-3, are described. Outputs to neurones L4-5 are excitatory and transmit tonically, whereas reciprocal connections among the three L1-3 neurones are inhibitory and incapable of transmission for longer than a few milliseconds. The tonically transmitting synapses are located in the lateral ocellar tract and are made between the axons of L1-3, which do not receive inputs, and short branches of L4-5, which make no outputs. Each excitatory connection is composed of a few hundred discrete anatomical synapses, each characterised by a bar-shaped presynaptic density which is 0.15-1.5 microns in length and associated with a large number of round synaptic vesicles. Two postsynaptic profiles are apposed to each presynaptic density. Associated with tonic synapses are abundant invaginations of the presynaptic membrane. Synapses of the reciprocal, inhibitory, phasic connections occur in the protocerebral arbors of L1-3, among numerous output synapses of these neurones. Each phasic connection is composed of a few tens of discrete anatomical synapses. Each bar-shaped presynaptic density is associated with two postsynaptic profiles, and is 0.1-1.0 microns long. Compared with the tonic, excitatory connection, there are fewer vesicles and fewer invaginations of the presynaptic membrane associated with each synapse.     

Competition regulates the efficacy of an identified synapse in crickets

The efficacy of the synaptic contact between an identified sensory neuron and an identified interneuron in crickets is increased when neighboring afferent synapses are removed early in postembryonic life. The physiological changes are correlated with changes in the structure of the presynaptic neuron's axonal arborizations: When neighboring axons are destroyed, there is a shift of the remaining axonal arbors into deafferented regions and an increase in the number of putative contacts with the postsynaptic neuron. Changes in the structure of the presynaptic neuron also directly affect the probability of formation of this synaptic connection. The connection was found in 67% of the control specimens, but it was present in 100% of the partially deafferented specimens. The results demonstrate that interactions between growing sensory neurons can influence both the probability of synapse formation and the strength of those connections. This is the first case in which the effects of competition on the structure of a single, identified, presynaptic neuron can be directly related to its synaptic efficacy.     

Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit

Throughout the nervous system, the convergence of two or more presynaptic inputs on a target cell is commonly observed. The question we ask here is to what extent converging inputs influence each other''s structural and functional synaptic plasticity. In complex circuits, isolating individual inputs is difficult because postsynaptic cells can receive thousands of inputs. An ideal model to address this question is the Drosophila larval neuromuscular junction (NMJ) where each postsynaptic muscle cell receives inputs from two glutamatergic types of motor neurons (MNs), known as 1b and 1s MNs. Notably, each muscle is unique and receives input from a different combination of 1b and 1s MNs; we surveyed multiple muscles for this reason. Here, we identified a cell-specific promoter that allows ablation of 1s MNs postinnervation and measured structural and functional responses of convergent 1b NMJs using microscopy and electrophysiology. For all muscles examined in both sexes, ablation of 1s MNs resulted in NMJ expansion and increased spontaneous neurotransmitter release at corresponding 1b NMJs. This demonstrates that 1b NMJs can compensate for the loss of convergent 1s MNs. However, only a subset of 1b NMJs showed compensatory evoked neurotransmission, suggesting target-specific plasticity. Silencing 1s MNs led to similar plasticity at 1b NMJs, suggesting that evoked neurotransmission from 1s MNs contributes to 1b synaptic plasticity. Finally, we genetically blocked 1s innervation in male larvae and robust 1b synaptic plasticity was eliminated, raising the possibility that 1s NMJ formation is required to set up a reference for subsequent synaptic perturbations.SIGNIFICANCE STATEMENT In complex neural circuits, multiple convergent inputs contribute to the activity of the target cell, but whether synaptic plasticity exists among these inputs has not been thoroughly explored. In this study, we examined synaptic plasticity in the structurally and functionally tractable Drosophila larval neuromuscular system. In this convergent circuit, each muscle is innervated by a unique pair of motor neurons. Removal of one neuron after innervation causes the adjacent neuron to increase neuromuscular junction outgrowth and functional output. However, this is not a general feature as each motor neuron differentially compensates. Further, robust compensation requires initial coinnervation by both neurons. Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states.     

Molecular mechanisms of synaptic specificity

Synapses are specialized junctions that mediate information flow between neurons and their targets. A striking feature of the nervous system is the specificity of its synaptic connections: an individual neuron will form synapses only with a small subset of available presynaptic and postsynaptic partners. Synaptic specificity has been classically thought to arise from homophilic or heterophilic interactions between adhesive molecules acting across the synaptic cleft. Over the past decade, many new mechanisms giving rise to synaptic specificity have been identified. Synapses can be specified by secreted molecules that promote or inhibit synaptogenesis, and their source can be a neighboring guidepost cell, not just presynaptic and postsynaptic neurons. Furthermore, lineage, fate, and timing of development can also play critical roles in shaping neural circuits. Future work utilizing large-scale screens will aim to elucidate the full scope of cellular mechanisms and molecular players that can give rise to synaptic specificity.     

Passive dendritic integration heavily affects spiking dynamics of recurrent networks.

According to dendritic cable theory, proximal synapses give rise to inputs with short delay, high amplitude, and short duration. In contrast, inputs from distal synapses have long delays, low amplitude, and long duration. Nevertheless, large scale neural networks are seldom built with realistically layered synaptic architectures and corresponding electrotonic parameters. Here, we use a simple model to investigate the spike response dynamics of networks with different electrotonic structures. The networks consist of a layer of neurons receiving a sparse feedforward projection from a set of inputs, as well as sparse recurrent connections from within the layer. Firing patterns are set in the inputs, and recorded from the neuron (output) layer. The feedforward and recurrent synapses are independently set as proximal or distal, representing dendritic connections near or far from the soma, respectively. Analyses of firing dynamics indicate that recurrent distal synapses tend to concentrate network activity in fewer neurons, while proximal recurrent synapses result in a more homogeneous activity distribution. In addition, when the feedforward input is regular (spiking or bursting) and asynchronous, the output is regular if recurrent synapses are more distal than feedforward ones, and irregular in the opposite configuration. Finally, the amplitude of network fluctuations in response to asynchronous input is lower if feedforward and recurrent synapses are electrotonically distant from one another (in either configuration). In conclusion, electrotonic effects reflecting different dendritic positions of synaptic inputs significantly influence network dynamics.     

Inhibitory short‐term plasticity modulates neuronal activity in the rat entopeduncular nucleus in vitro

The entopeduncular nucleus (EP) is one of the basal ganglia output nuclei integrating synaptic information from several pathways within the basal ganglia. The firing of EP neurons is modulated by two streams of inhibitory synaptic transmission, the direct pathway from the striatum and the indirect pathway from the globus pallidus. These two inhibitory pathways continuously modulate the firing of EP neurons. However, the link between these synaptic inputs to neuronal firing in the EP is unclear. To investigate this input–output transformation we performed whole‐cell and perforated‐patch recordings from single neurons in the entopeduncular nucleus in rat brain slices during repetitive stimulation of the striatum and the globus pallidus at frequencies within the in vivo activity range of these neurons. These recordings, supplemented by compartmental modelling, showed that GABAergic synapses from the striatum, converging on EP dendrites, display short‐term facilitation and that somatic or proximal GABAergic synapses from the globus pallidus show short‐term depression. Activation of striatal synapses during low presynaptic activity decreased postsynaptic firing rate by continuously increasing the inter‐spike interval. Conversely, activation of pallidal synapses significantly affected postsynaptic firing during high presynaptic activity. Our data thus suggest that low‐frequency striatal output may be encoded as progressive phase shifts in downstream nuclei of the basal ganglia while high‐frequency pallidal output may continuously modulate EP firing.     

Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex

Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here, we demonstrate how the timescales associated with respiratory frequency, spike timing, and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase-locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex.     

Presynaptic gating of postsynaptically expressed plasticity at mature thalamocortical synapses

Thalamocortical (TC) projections provide the major pathway for ascending sensory information to the mammalian neocortex. Arrays of these projections form synaptic inputs on thalamorecipient neurons, thus contributing to the formation of receptive fields (RFs) in sensory cortices. Experience-dependent plasticity of RFs persists throughout an organism's life span but in adults requires activation of cholinergic inputs to the cortex. In contrast, synaptic plasticity at TC projections is limited to the early postnatal period. This disconnect led to the widespread belief that TC synapses are the principal site of RF plasticity only in neonatal sensory cortices, but that they lose this plasticity upon maturation. Here, we tested an alternative hypothesis that mature TC projections do not lose synaptic plasticity but rather acquire gating mechanisms that prevent the induction of synaptic plasticity. Using whole-cell recordings and direct measures of postsynaptic and presynaptic activity (two-photon glutamate uncaging and two-photon imaging of the FM 1-43 assay, respectively) at individual synapses in acute mouse brain slices that contain the auditory thalamus and cortex, we determined that long-term depression (LTD) persists at mature TC synapses but is gated presynaptically. Cholinergic activation releases presynaptic gating through M(1) muscarinic receptors that downregulate adenosine inhibition of neurotransmitter release acting through A(1) adenosine receptors. Once presynaptic gating is released, mature TC synapses can express LTD postsynaptically through group I metabotropic glutamate receptors. These results indicate that synaptic plasticity at TC synapses is preserved throughout the life span and, therefore, may be a cellular substrate of RF plasticity in both neonate and mature animals.     

Nicotine recruits glutamate receptors to postsynaptic sites

Cholinergic neurons project throughout the nervous system and activate nicotinic receptors to modulate synaptic function in ways that shape higher order brain function. The acute effects of nicotinic signaling on long-term synaptic plasticity have been well-characterized. Less well understood is how chronic exposure to low levels of nicotine, such as those encountered by habitual smokers, can alter neural connections to promote addiction and other lasting behavioral effects. We show here that chronic exposure of hippocampal neurons in culture to low levels of nicotine recruits AMPA and NMDA receptors to the cell surface and sequesters them at postsynaptic sites. The receptors include GluA2-containing AMPA receptors, which are responsible for most of the excitatory postsynaptic current mediated by AMPA receptors on the neurons, and include NMDA receptors containing GluN1 and GluN2B subunits. Moreover, we find that the nicotine treatment also increases expression of the presynaptic component synapsin 1 and arranges it in puncta juxtaposed to the additional AMPA and NMDA receptor puncta, suggestive of increases in synaptic contacts. Consistent with increased synaptic input, we find that the nicotine treatment leads to an increase in the excitatory postsynaptic currents mediated by AMPA and NMDA receptors. Further, the increases skew the ratio of excitatory-to-inhibitory input that the cell receives, and this holds both for pyramidal neurons and inhibitory neurons in the hippocampal CA1 region. The GluN2B-containing NMDA receptor redistribution at synapses is associated with a significant increase in GluN2B phosphorylation at Tyr1472, a site known to prevent GluN2B endocytosis. These results suggest that chronic exposure to low levels of nicotine not only alters functional connections but also is likely to change excitability levels across networks. Further, it may increase the propensity for synaptic plasticity, given the increase in synaptic NMDA receptors.     

The formation of terminal fields in the absence of competitive interactions among primary motoneurons in the zebrafish

To make specific synaptic connections, projection neurons extend neurites to regions containing appropriate targets, then form synapses with the correct type and number of target cells. To investigate the mechanisms controlling this process, we have studied the formation of motoneuronal terminal fields in live zebrafish embryos. The primary motoneurons of the zebrafish are identifiable as individuals and innervate neighboring but mutually exclusive territories. To study the first week of their development, which includes embryonic and early larval stages, we labeled identified motoneurons with fluorescent dyes and made sequential observations of the axonal branches of individual neurons. We assessed the roles of competitive interactions and synapse elimination in the formation of specific synapses by identified neurons that innervate neighboring territories. Our results demonstrate that primary motoneurons establish their cell-specific terminal fields primarily by directed outgrowth of branches and formation of neuromuscular junctions almost exclusively on appropriate muscle fibers, rather than by overproduction and selective elimination of inappropriate branches. Retraction of the few branches that are inappropriately placed, though correlated in time with the ingrowth of branches from appropriate motoneurons, occurs independently of the influences of these other cells and when neuromuscular transmission is blocked. We suggest that, similar to the way in which they pioneer peripheral nerve pathways, primary motoneurons establish their cell-specific terminal fields using mechanisms that operate independently of activity and competition. The target or substrate interactions that are likely to instruct directed growth-cone navigation may be similar to the interactions that determine the locations of territorial borders and that instruct the retraction of misplaced branches.     

Cholinergic function in cultures of mouse spinal cord neurons

Cholinergic synapses formed in cultures of fetal mouse spinal cord (SC) and superior cervical ganglion (SCG) were studied using intracellular and extracellular stimulation and recording as well as immunohistochemical staining for choline acetyltransferase (ChAT). Dissociated SC neurons and SC explants exhibited cholinergic terminals on SCG and SC neurons as demonstrated by ChAT immunoreactivity. Intracellular recordings showed that cholinergic inputs to SCG neurons were relatively common and that these synaptic inputs were blocked by the nicotinic acetylcholine (ACh) receptor blocker, tubocurarine. A comparison of three preparations indicated that the incidence of cholinergic activity recorded in SCG neurons was significantly higher in co-cultures of SCG with spinal cord ventral horn (VH) neurons grown on a substrate of non-neuronal cells from cerebral cortex, than in co-cultures with VH alone or with SC and dorsal root ganglion cells. Consistency between cholinergic physiology and staining for ChAT-positive terminals on SCG neuronal somata was obtained in cultures of SC explants grown with dissociated SCG. Application of acetylcholine, muscarine, and/or vasoactive intestinal polypeptide (VIP) produced slow excitation of SC neurons. Fast excitatory cholinergic interactions between SC neurons were not observed. Excitatory synaptic interactions between SC neurons were augmented by ACh or muscarine, while inhibitory synaptic interactions were diminished. Both types of synaptic modulation probably were produced by a presynaptic mechanism. Acetylcholine or muscarine affected synaptic interactions between SC neurons in only one-third of the synaptic connections tested, suggesting that the incidence of presynaptically cholinoceptive SC neurons is low in dissociated cell cultures. The experimental results show that a culture system incorporating dissociated fetal mouse SC neurons or explants of SC with sympathetic ganglion neurons expresses both nicotinic and muscarinic cholinergic function.     

Embryonic development of synapses on spiking local interneurones in locust.

The development of synapses on an identified population of spiking local interneurones in the thoracic ganglia of embryonic locusts was examined by means of intracellular horseradish peroxidase injection and electron microscopy. In adult locusts, spiking local interneurones of the midline group receive direct inputs onto a ventral field of branches from leg mechanosensory afferents and in turn make output synapses, mainly from a dorsal field of branches, directly upon leg motor neurones, nonspiking local interneurones, and intersegmental interneurones. The aim of this study is to examine the development of these connections. These interneurones are born relatively late in embryogenesis and are not identifiable until approximately 55% of development. At this time (55-60%) only simple filopodial contacts or punctate contacts are evident between the stained interneurones and other neurones. By 65-70% embryogenesis, vesicles are found adjacent to regions where apposed membranes are symmetrically thickened with amorphous electron-dense material. These symmetrical contacts lack distinct presynaptic bar-shaped densities and therefore, are not considered to be synapses. At this stage, the interneurones do not produce action potentials upon intracellular injection of depolarising current. Morphologically identifiable synapses, with vesicles, a presynaptic bar, and relatively little postsynaptic density, are first evident at 70-75%, coincident with the time of arrival of the majority of leg mechanosensory afferents into the central nervous system. At this stage, action potentials and synaptic potentials are also recorded for the first time. The midline spiking interneurones thus become electrically excitable when synapses are first recognisable, at approximately 70% embryogenesis. Most of the synapses found on the interneurones are outputs. The ratio of outputs to inputs on ventral branches is 7.5:1 which contrasts markedly to the adult ratio of 1:2. By 85-90%, output synapses still predominate on the ventral branches, but the ratio of outputs to inputs is reduced to almost 2:1. Dorsal branches have predominantly output synapses throughout embryogenesis. The ratio of dorsal outputs to inputs at 85-90% is 8.5:1 which compares with the adult ratio of 6.5:1. At this stage, action potentials and synaptic activity are always recorded.     

Dynamic synapse: A new concept of neural representation and computation

Presynaptic mechanisms influencing the probability of neurotransmitter release from an axon terminal, such as facilitation, augmentation, and presynaptic feedback inhibition, are fundamental features of biological neurons and are cardinal physiological properties of synaptic connections in the hippocampus. The consequence of these presynaptic mechanisms is that the probability of release becomes a function of the temporal pattern of action potential occurrence, and hence, the strength of a given synapse varies upon the arrival of each action potential invading the terminal region. From the perspective of neural information processing, the capability of dynamically tuning the synaptic strength as a function of the level of neuronal activation gives rise to a significant representational and processing power of temporal spike patterns at the synaptic level. Furthermore, there is an exponential growth in such computational power when the specific dynamics of presynaptic mechanisms varies quantitatively across axon terminals of a single neuron, a recently established characteristic of hippocampal synapses. During learning, alterations in the presynaptic mechanisms lead to different pattern transformation functions, whereas changes in the postsynaptic mechanisms determine how the synaptic signals are to be combined. We demonstrate the computational capability of dynamic synapses by performing speech recognition from unprocessed, noisy raw waveforms of words spoken by multiple speakers with a simple neural network consisting of a small number of neurons connected with synapses incorporating dynamically determined probability of release. The dynamics included in the model are consistent with available experimental data on hippocampal neurons in that parameter values were chosen so as to be consistent with time constants of facilitative and inhibitory processes governing the dynamics of hippocampal synaptic transmission studied using nonlinear systems analytic procedures. © 1997 Wiley-Liss, Inc.     

Retrograde signalling with nitric oxide at neocortical synapses

Long-term changes of synaptic transmission in slices of rat visual cortex were induced by intracellular tetanization: bursts of short depolarizing pulses applied through the intracellular electrode without concomitant presynaptic stimulation. Long-term synaptic changes after this purely postsynaptic induction were associated with alterations of release indices, thus providing a case for retrograde signalling at neocortical synapses. Both long-term potentiation and long-term depression were accompanied by presynaptic changes, indicating that retrograde signalling can achieve both up- and down-regulation of transmitter release. The direction and the magnitude of the amplitude changes induced by a prolonged intracellular tetanization depended on the initial properties of the input. The inputs with initially high paired-pulse facilitation (PPF) ratio, indicative of low release probability, were most often potentiated. The inputs with initially low PPF ratio, indicative of high release probability, were usually depressed or did not change. Thus, prolonged postsynaptic activity can lead to normalization of the weights of nonactivated synapses. The dependence of polarity of synaptic modifications on initial PPF disappeared when plastic changes were induced with a shorter intracellular tetanization, or when the NO signalling pathway was interrupted by inhibition of NO synthase activity or by application of NO scavengers. This indicates that the NO-dependent retrograde signalling system has a relatively high activation threshold. Long-term synaptic modifications, induced by a weak postsynaptic challenge or under blockade of NO signalling, were nevertheless associated with presynaptic changes. This suggests the existence of another retrograde signalling system, additional to the high threshold, NO-dependent system. Therefore, our data provide a clear case for retrograde signalling at neocortical synapses and indicate that multiple retrograde signalling systems, part of which are NO-dependent, are involved.     

Microglia‐derived purines modulate mossy fibre synaptic transmission and plasticity through P2X4 and A1 receptors

Recent data have provided evidence that microglia, the brain‐resident macrophage‐like cells, modulate neuronal activity in both physiological and pathophysiological conditions, and microglia are therefore now recognized as synaptic partners. Among different neuromodulators, purines, which are produced and released by microglia, have emerged as promising candidates to mediate interactions between microglia and synapses. The cellular effects of purines are mediated through a large family of receptors for adenosine and for ATP (P2 receptors). These receptors are present at brain synapses, but it is unknown whether they can respond to microglia‐derived purines to modulate synaptic transmission and plasticity. Here, we used a simple model of adding immune‐challenged microglia to mouse hippocampal slices to investigate their impact on synaptic transmission and plasticity at hippocampal mossy fibre (MF) synapses onto CA3 pyramidal neurons. MF–CA3 synapses show prominent forms of presynaptic plasticity that are involved in the encoding and retrieval of memory. We demonstrate that microglia‐derived ATP differentially modulates synaptic transmission and short‐term plasticity at MF–CA3 synapses by acting, respectively, on presynaptic P2X₄ receptors and on adenosine A₁ receptors after conversion of extracellular ATP to adenosine. We also report that P2X₄ receptors are densely located in the mossy fibre tract in the dentate gyrus–CA3 circuitry. In conclusion, this study reveals an interplay between microglia‐derived purines and MF–CA3 synapses, and highlights microglia as potent modulators of presynaptic plasticity.     

Ectopic expression of NCAM in skeletal muscle of transgenic mice results in terminal sprouting at the neuromuscular junction and altered structure but not function

The neuromuscular system provides an excellent model for the analysis of molecular interactions involved in the development and plasticity of synaptic contacts. The neural cell adhesion molecule (NCAM) is believed to be involved in the development and plasticity of the neuromuscular junction, in particular the axonal sprouting response observed in paralyzed and denervated muscle. In order to explore the role of myofiber NCAM in modulating the differentiation of motor neurons, we generated transgenic mice expressing a GPI-anchored NCAM isoform that is normally found in developing and denervated muscle, under the control of a skeletal muscle-specific promoter. This results in the constitutive expression of NCAM at postnatal ages, a time when the endogenous mouse NCAM is absent from the myofiber. We found that a significant number of neuromuscular junctions in adult transgenic animals displayed terminal sprouting (>20%) reminiscent of that elicited in response to cessation of neuromuscular activity. Additionally, a significant increase in the size and complexity of neuromuscular synapses as a result of extensive intraterminal sprouting was detected. Electrophysiological studies, however, revealed no significant alterations of neuromuscular transmission at this highly efficient synapse. Sprouting in response to paralysis or following nerve crush was also significantly enhanced in transgenic animals. These results suggest that in this ectopic expression model NCAM can directly modulate synaptic structure and motor neuron-muscle interactions. The results contrast with knockout experiments of the NCAM gene, where very limited changes in the neuromuscular system were observed.     

Afferent-specific modulation of short-term synaptic plasticity by neurotrophins in dentate gyrus

Neurotrophins modulate synaptic transmission and plasticity in the adult brain. We here show a novel feature of this synaptic modulation, i.e. that two populations of excitatory synaptic connections to granule cells in the dentate gyrus, lateral perforant path (LPP) and medial perforant path (MPP), are differentially influenced by the neurotrophins BDNF and NT-3. Using field recordings and whole-cell patch-clamp recordings in hippocampal slices, we found that paired-pulse (PP) depression at MPP-granule cell synapses was impaired in BDNF knock-out (+/-) mice, but PP facilitation at LPP synapses to the same cells was not impaired. In accordance, scavenging of endogenous BDNF with TrkB-IgG fusion protein also impaired PP depression at MPP-granule cell synapses, but not PP facilitation at LPP-granule cell synapses. Conversely, in NT-3+/- mice, PP facilitation was impaired at LPP-granule cell synapses whilst PP depression at MPP-granule cell synapses was unaffected. These deficits could be reversed by application of exogenous neurotrophins in an afferent-specific manner. Our data suggest that BDNF and NT-3 differentially regulate the synaptic impact of different afferent inputs onto single target neurons in the CNS.     

Synaptic efficacy is commonly regulated within a nervous system and predicts individual differences in learning

The hypothesis that an individual's capacity for learning might be predicted or influenced by basal levels of synaptic efficacy has eluded empirical tests, owing in part to the inability to compare between animals single identified synaptic responses in the mammalian brain. To overcome this limitation, we have focused our analysis on the invertebrate Hermissenda, whose nervous system is composed of identifiable cells and synaptic interactions. Hermissenda were exposed to paired presentations of light and rotation such that the light came to elicit a learned defensive motor response. An animal's rate of learning was strongly correlated with the amplitude of the synaptic potential evoked in that animal's visual (light sensitive) receptors in response to stimulation of presynaptic vestibular (rotation sensitive) hair cells. In naive animals, strong correlations between the amplitude of both inhibitory and excitatory synaptic potentials were observed between synapses distributed throughout an animal's nervous system, and this conservation of synaptic efficacy was largely attributable to a common influence on transmitter release. These observations suggest that basal synaptic efficacy may be uniformly regulated throughout a nervous system, and provide direct evidence that the basal efficacy of synaptic transmission predicts, and possibly contributes to, individual differences between animals in their capacity to learn.