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Biomedical subjects

M Poo

Publications and source records attributed to M Poo.

At least 19 recordsLinked to original sources
PubMed2001

Retrograde signaling at central synapses.

Transcellular retrograde signaling from the postsynaptic target cell to the presynaptic neuron plays critical roles in the formation, maturation, and plasticity of synaptic connections. We here review recent progress in our understanding of the retrograde signaling at developing central synapses. Three forms of potential retrograde signals-membrane-permeant factors, membrane-bound factors, and secreted factors-have been implicated at both developing and mature synapses. Although many of these signals may be active constitutively, retrograde factors produced in association with activity-dependent synaptic plasticity, e.g., long-term potentiation and long-term depression, are of particular interest, because they may induce modification of neuronal excitability and synaptic transmission, functions directly related to the processing and storage of information in the nervous system.

Animals↗
PubMed2001

Emergence of input specificity of ltp during development of retinotectal connections in vivo.

Input specificity of activity-induced synaptic modification was examined in the developing Xenopus retinotectal connections. Early in development, long-term potentiation (LTP) induced by theta burst stimulation (TBS) at one retinal input spreads to other unstimulated converging inputs on the same tectal neuron. As the animal develops, LTP induced by the same TBS becomes input specific, a change that correlates with the increased complexity of tectal dendrites and more restricted distribution of dendritic Ca(2+) evoked by each retinal input. In contrast, LTP induced by 1 Hz correlated pre- and postsynaptic spiking is input specific throughout the same developmental period. Thus, input specificity of LTP emerges with neural development and depends on the pattern of synaptic activity.

Action Potentials↗
PubMed2001

GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition.

GABA is the main inhibitory neurotransmitter in the adult brain. Early in development, however, GABAergic synaptic transmission is excitatory and can exert widespread trophic effects. During the postnatal period, GABAergic responses undergo a switch from being excitatory to inhibitory. Here, we show that the switch is delayed by chronic blockade of GABA(A) receptors, and accelerated by increased GABA(A) receptor activation. In contrast, blockade of glutamatergic transmission or action potentials has no effect. Furthermore, GABAergic activity modulated the mRNA levels of KCC2, a K(+)-Cl(-) cotransporter whose expression correlates with the switch. Finally, we report that GABA can alter the properties of depolarization-induced Ca(2+) influx. Thus, GABA acts as a self-limiting trophic factor during neural development.

Action Potentials↗
PubMed2001

Filopodial calcium transients promote substrate-dependent growth cone turning.

Filopodia that extend from neuronal growth cones sample the environment for extracellular guidance cues, but the signals they transmit to growth cones are unknown. Filopodia were observed generating localized transient elevations of intracellular calcium ([Ca2+]i) that propagate back to the growth cone and stimulate global Ca2+ elevations. The frequency of filopodial Ca2+ transients was substrate-dependent and may be due in part to influx of Ca2+ through channels activated by integrin receptors. These transients slowed neurite outgrowth by reducing filopodial motility and promoted turning when stimulated differentially within filopodia on one side of the growth cone. These rapid signals appear to serve both as autonomous regulators of filopodial movement and as frequency-coded signals integrated within the growth cone and could be a common signaling process for many motile cells.

Animals↗
PubMed2001

Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.

Netrins stimulate and orient axon growth through a mechanism requiring receptors of the DCC family. It has been unclear, however, whether DCC proteins are involved directly in signaling or are mere accessory proteins in a receptor complex. Further, although netrins bind cells expressing DCC, direct binding to DCC has not been demonstrated. Here we show that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation.

Animals↗
PubMed2001

Electrical activity modulates growth cone guidance by diffusible factors.

Brief periods of electrical stimulation of cultured Xenopus spinal neurons resulted in a marked alteration in the turning responses of the growth cone induced by gradients of attractive or repulsive guidance cues. Netrin-1-induced attraction was enhanced, and the repulsion induced by myelin-associated glycoprotein (MAG) or myelin membrane fragments was converted to attraction. The effect required the presence of extracellular Ca(2+) during electrical stimulation and appeared to be mediated by an elevation of both cytoplasmic Ca(2+) and cAMP. Thus, electrical activity may influence the axonal path finding of developing neurons, and intermittent electrical stimulation may be effective in promoting nerve regeneration after injury.

Animals↗
PubMed2001

The cell biology of neuronal navigation.

Morphogenesis of the nervous system requires the directed migration of postmitotic neurons to designated locations in the nervous system and the guidance of axon growth cones to their synaptic targets. Evidence suggests that both forms of navigation depend on common guidance molecules, surface receptors and signal transduction pathways that link receptor activation to cytoskeletal reorganization. Future challenges remain not only in identifying all the components of the signalling pathways, but also in understanding how these pathways achieve signal amplification and adaptation-two essential cellular processes for neuronal navigation.

Animals↗
PubMed2001

Synaptic modification by correlated activity: Hebb's postulate revisited.

Correlated spiking of pre- and postsynaptic neurons can result in strengthening or weakening of synapses, depending on the temporal order of spiking. Recent findings indicate that there are narrow and cell type-specific temporal windows for such synaptic modification and that the generally accepted input- (or synapse-) specific rule for modification appears not to be strictly adhered to. Spike timing-dependent modifications, together with selective spread of synaptic changes, provide a set of cellular mechanisms that are likely to be important for the development and functioning of neural networks. When an axon of cell A is near enough to excite cell B or repeatedly or consistently takes part in firing it, some growth or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased.

Animals↗
PubMed2000

Selective presynaptic propagation of long-term potentiation in defined neural networks.

Induction of long-term potentiation (LTP) of the synaptic connection between two hippocampal glutamatergic neurons in a neural network formed in cell culture resulted in a specific pattern of potentiation at other connections within the network. We found that potentiation propagated from the site of induction retrogradely to glutamatergic or GABAergic synapses received by the dendrites of the presynaptic neuron and laterally to those made by its axonal collaterals onto other glutamatergic cells. In contrast, synapses made by the same presynaptic neuron onto GABAergic cells were not affected, and there was no postsynaptic lateral or forward propagation to other synapses received or made by the postsynaptic neuron. In addition, there was no secondary propagation to synapses not directly associated with the presynaptic neuron. Both induction and propagation of LTP required correlated spiking of the postsynaptic cell as well as the activation of the NMDA subtype of glutamate receptors. Such selective propagation suggests the existence of a long-range cytoplasmic signaling within the presynaptic neuron, leading to a specific pattern of coordinated potentiation along excitatory pathways in a neural network.

Animals↗
PubMed2000

Calcium signalling in the guidance of nerve growth by netrin-1.

Pathfinding by growing axons in the developing nervous system is guided by diffusible or bound factors that attract or repel the axonal growth cone. The cytoplasmic signalling mechanisms that trigger the responses of the growth cone to guidance factors are mostly unknown. Previous studies have shown that the level and temporal patterns of cytoplasmic Ca2+ can regulate the rate of growth-cone extension in vitro and in vivo. Here we report that Ca2+ also mediates the turning behaviour of the growth cones of cultured Xenopus neurons that are induced by an extracellular gradient of netrin-1, an established diffusible guidance factor in vivo. The netrin-1-induced turning response depends on Ca2+ influx through plasma membrane Ca2+ channels, as well as Ca2+-induced Ca2+ release from cytoplasmic stores. Reduction of Ca2+ signals by blocking either of these two Ca2+ sources converted the netrin-1-induced response from attraction to repulsion. Activation of Ca2+-induced Ca2+ release from internal stores with a gradient of ryanodine in the absence of netrin-1 was sufficient to trigger either attractive or repulsive responses, depending on the ryanodine concentration used. These results support the model that cytoplasmic Ca2+ signals mediate growth-cone guidance by netrin-1, and different patterns of Ca2+ elevation trigger attractive and repulsive turning responses.

Animals↗
PubMed2000

The neurotrophin hypothesis for synaptic plasticity.

The neurotrophin hypothesis proposes that neurotrophins participate in activity-induced modification of synaptic transmission. Increasingly, evidence indicates that the synthesis, secretion and actions of neurotrophins on synaptic transmission are regulated by electrical activity and that neurotrophins themselves can acutely modify synaptic efficacy. Neurotrophins appear to exert either a permissive or instructive role on activity-dependent synaptic potentiation and depression, which depends on the particular synaptic connections and developmental stages. The characteristics of synaptic changes that are induced by neurotrophins suggest that this family of proteins is crucial for providing a molecular background in which activity-dependent plasticity can occur at selective synaptic sites within the neural network.

Animals↗
PubMed2000

Postsynaptic target specificity of neurotrophin-induced presynaptic potentiation.

The role of the target cell in neurotrophin-induced modifications of glutamatergic synaptic transmission was examined in cultured hippocampal neurons. Brain-derived neurotrophic factor (BDNF) induced rapid and persistent potentiation of evoked glutamate release when the postsynaptic neuron was glutamatergic, or excitatory (E-->E), but not when it was GABAergic, or inhibitory (E-->1). This target-specific action of BDNF was also found at divergent outputs of a single presynaptic neuron innervating both glutamatergic and GABAergic neurons, suggesting that individual terminals can be independently modified. Surprisingly, BDNF increased the frequency of miniature postsynaptic currents at both E-->E and E-->I, although it had no effect on evoked currents at E-->I. Finally, potentiation by neurotrophin-3 (NT-3) was also target specific. The selective effect at E-->E suggests that retrograde signaling by the postsynaptic target cell endows a localized presynaptic action of neurotrophins.

Animals↗
PubMed2000

Visual input induces long-term potentiation of developing retinotectal synapses.

Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections.

2-Amino-5-phosphonovalerate↗
PubMed2000

Enhancement of presynaptic neuronal excitability by correlated presynaptic and postsynaptic spiking.

Use-dependent modifications, such as long-term potentiation (LTP) of synaptic efficacy, are believed to be essential for information storage in the nervous system. Repetitive correlated spiking of presynaptic and postsynaptic neurons can induce LTP at excitatory glutamatergic synapses. In cultured hippocampal neurons, we show that repetitive correlated activity also results in a rapid and persistent enhancement of presynaptic excitability, decreasing the threshold for spiking and reducing the variability of interspike intervals. Furthermore, we found that correlated activity modified sodium channel gating in the presynaptic neuron. This modification of presynaptic excitability required a temporal order between presynaptic and postsynaptic spiking and activation of postsynaptic NMDA receptors. Presynaptic inhibition of protein kinase C abolished the change in excitability without affecting LTP. Such rapid activity-dependent changes in the efficacy of presynaptic spiking may be involved in the processing and storage of information within the nervous system.

Action Potentials↗
PubMed1999

Distributed synaptic modification in neural networks induced by patterned stimulation.

Activity-dependent changes in synaptic efficacy or connectivity are critical for the development, signal processing and learning and memory functions of the nervous system. Repetitive correlated spiking of pre- and postsynaptic neurons can induce a persistent increase or decrease in synaptic strength, depending on the timing of the pre- and postsynaptic excitation. Previous studies on such synaptic modifications have focused on synapses made by the stimulated neuron. Here we examine, in networks of cultured hippocampal neurons, whether and how localized stimulation can modify synapses that are remote from the stimulated neuron. We found that repetitive paired-pulse stimulation of a single neuron for brief periods induces persistent strengthening or weakening of specific polysynaptic pathways in a manner that depends on the interpulse interval. These changes can be accounted for by correlated pre- and postsynaptic excitation at distant synaptic sites, resulting from different transmission delays along separate pathways. Thus, through such a 'delay-line' mechanism, temporal information coded in the timing of individual spikes can be converted into and stored as spatially distributed patterns of persistent synaptic modifications in a neural network.

Animals↗
PubMed1999

Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates.

In Drosophila, plexin A is a functional receptor for semaphorin-1a. Here we show that the human plexin gene family comprises at least nine members in four subfamilies. Plexin-B1 is a receptor for the transmembrane semaphorin Sema4D (CD100), and plexin-C1 is a receptor for the GPI-anchored semaphorin Sema7A (Sema-K1). Secreted (class 3) semaphorins do not bind directly to plexins, but rather plexins associate with neuropilins, coreceptors for these semaphorins. Plexins are widely expressed: in neurons, the expression of a truncated plexin-A1 protein blocks axon repulsion by Sema3A. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. We conclude that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.

3T3 Cells↗
PubMed1999

Activity-induced potentiation of developing neuromuscular synapses.

Electrical activity plays a critical role in shaping the structure and function of synaptic connections in the nervous system. In Xenopus nerve-muscle cultures, a brief burst of action potentials in the presynaptic neuron induced a persistent potentiation of neuromuscular synapses that exhibit immature synaptic functions. Induction of potentiation required an elevation of postsynaptic Ca2+ and expression of potentiation appeared to involve an increased probability of transmitter secretion from the presynaptic nerve terminal. Thus, activity-dependent persistent synaptic enhancement may reflect properties characteristic of immature synaptic connections, and bursting activity in developing spinal neurons may promote functional maturation of the neuromuscular synapse.

Action Potentials↗