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Mu-ming Poo

Publications and source records attributed to Mu-ming Poo.

At least 19 recordsLinked to original sources
PubMed2006

BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal.

The neural mechanism underlying the relapse to drug use after drug withdrawal is largely unknown. We found that after withdrawal from repeated cocaine exposure, excitatory synapses onto dopamine neurons in the ventral tegmental area (VTA) of the rat midbrain became highly susceptible to potentiation by weak presynaptic stimuli, an effect requiring endogenous brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling. The elevated BDNF expression in the VTA after cocaine withdrawal may prime these synapses for potentiation by cue-associated activity, triggering drug craving and relapse.

Animals↗
PubMed2006

Coincidence detection of synaptic inputs is facilitated at the distal dendrites after long-term potentiation induction.

Two major aspects of dendritic integration, coincidence detection and temporal integration, depend critically on the spatial and temporal properties of the dendritic summation of synaptic inputs. Neuronal activity capable of inducing synaptic long-term potentiation (LTP) leads to increased linearity of the spatial summation of synchronous EPSPs. Whether such activity can also modulate the temporal summation of EPSPs is unknown. In the present study, we examined the linearity of the summation of EPSPs spaced by different time intervals in hippocampal CA1 pyramidal neurons, before and after LTP induction. We found that LTP induction resulted in an increased linearity of summation of the potentiated input with another synchronous or asynchronous input, with a striking dendritic location-specific selectivity for the timing of the summed inputs. At distal dendrites, LTP induction led to an increased linearity of summation only for EPSPs arriving within 5 ms, thus favoring the summation of coincident inputs. In contrast, LTP induction at proximal dendrites increased the linearity of summation for EPSPs arriving within a time window of >20 ms. Furthermore, for synaptic inputs at the distal dendrite, enhanced spiking output after LTP induction was observed only for coincidently summed EPSPs, suggesting facilitated coincidence detection. In contrast, for proximal inputs, enhanced spiking output after LTP induction occurred for EPSPs arriving within a broader time window of approximately 20 ms, favoring temporal integration. Such dendritic location-dependent differential modulation of coincidence detection and temporal integration by neuronal activity represents a form of activity-dependent and domain-specific plasticity in the function of dendritic information processing.

Action Potentials↗
PubMed2006

Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDA receptors.

Local GABA (gamma-aminobutyric acid) circuits contribute to sensory experience-dependent refinement of neuronal connections in the developing nervous system, but whether GABAergic synapses themselves can be rapidly modified by sensory stimuli is largely unknown. Here we report that repetitive light stimuli or theta burst stimulation (TBS) of the optic nerve in the developing Xenopus retinotectal system induces long-term potentiation (LTP) of glutamatergic inputs but long-term depression (LTD) of GABAergic inputs to the same tectal neuron. The LTD is due to a reduction in presynaptic GABA release and requires activation of presynaptic NMDA (N-methyl-D-aspartate) receptors (NMDARs) and coincident high-level GABAergic activity. Thus, the presynaptic NMDAR may function as a coincidence detector for adjacent glutamatergic and GABAergic activities, leading to coordinated synaptic modification by sensory experience.

Animals↗
PubMed2005

Modulation of GABAergic transmission by activity via postsynaptic Ca2+-dependent regulation of KCC2 function.

Activity-induced modification of GABAergic transmission contributes to the plasticity of neural circuits. In the present work we found that prolonged postsynaptic spiking of hippocampal neurons led to a shift in the reversal potential of GABA-induced Cl- currents (E(Cl)) toward positive levels in a duration- and frequency-dependent manner. This effect was abolished by blocking cytosolic Ca2+ elevation and mimicked by releasing Ca2+ from internal stores. Activity- and Ca2+-induced E(Cl) shifts were larger in mature neurons, which express the K-Cl cotransporter KCC2 at high levels, and inhibition of KCC2 occluded the shifts. Overexpression of KCC2 in young cultured neurons, which express lower levels of KCC2 and have a more positive E(Cl), resulted in hyperpolarized E(Cl) similar to that of mature cells. Importantly, these young KCC2-expressing neurons became responsive to neuronal spiking and Ca2+ elevation by showing positive E(Cl) shifts. Thus, repetitive postsynaptic spiking reduces the inhibitory action of GABA through a Ca2+-dependent downregulation of KCC2 function.

Action Potentials↗
PubMed2005

Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons.

Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours. Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine. Here we report that, following repeated exposure to cocaine in vivo, excitatory synapses to rat VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre- and postsynaptic activity. This facilitated LTP induction is caused by cocaine-induced reduction of GABA(A) (gamma-aminobutyric acid) receptor-mediated inhibition of these dopamine neurons. In midbrain slices from rats treated with saline or a single dose of cocaine, LTP could not be induced in VTA dopamine neurons unless GABA-mediated inhibition was reduced by bicuculline or picrotoxin. However, LTP became readily inducible in slices from rats treated repeatedly with cocaine; this LTP induction was prevented by enhancing GABA-mediated inhibition using diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABA-mediated synaptic currents and increased the probability of spike initiation in VTA dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in the VTA may be important for the formation of drug-associated memory.

Animals↗
PubMed2005

Agrin regulates growth cone turning of Xenopus spinal motoneurons.

The pivotal role of agrin in inducing postsynaptic specializations at neuromuscular junctions has been well characterized. Increasing evidence suggests that agrin is also involved in neuronal development. In this study, we found that agrin inhibited neurite extension and, more importantly, a gradient of agrin induced repulsive growth-cone turning in cultured Xenopus spinal neurons. Incubation with a neutralizing antibody to agrin or expression of the extracellular domain of muscle-specific kinase, a component of the agrin receptor complex, abolished these effects of agrin. Agrin-induced repulsive growth-cone turning requires the activity of PI3-kinase and Ca2+ signaling. In addition, the expression of dominant-negative Rac1 inhibited neurite extension and blocked agrin-mediated growth-cone turning. Taken together, our findings suggest that agrin regulates neurite extension and provide evidence for an unanticipated role of agrin in growth-cone steering in developing neurons.

Agrin↗
PubMed2005

Activity-dependent matching of excitatory and inhibitory inputs during refinement of visual receptive fields.

The receptive field (RF) of single visual neurons undergoes progressive refinement during development. It remains largely unknown how the excitatory and inhibitory inputs on single developing neurons are refined in a coordinated manner to allow the formation of functionally correct circuits. Using whole-cell voltage-clamp recording from Xenopus tectal neurons, we found that RFs determined by excitatory and inhibitory inputs in more mature tectal neurons are spatially matched, with each spot stimulus evoking balanced synaptic excitation and inhibition. This emerges during development through a gradual reduction in the RF size and a transition from disparate to matched topography of excitatory and inhibitory inputs to the tectal neurons. Altering normal spiking activity of tectal neurons by either blocking or elevating GABA(A) receptor activity significantly impeded the developmental reduction and topographic matching of RFs. Thus, appropriate inhibitory activity is essential for the coordinated refinement of excitatory and inhibitory connections.

Action Potentials↗
PubMed2005

Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones.

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca2+-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca2+/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca2+ signals triggered by guidance factors to downstream cytoskeletal rearrangements.

Animals↗
PubMed2004

Calcium mediates bidirectional growth cone turning induced by myelin-associated glycoprotein.

Cytoplasmic second messengers, Ca2+ and cAMP, regulate nerve growth cone turning responses induced by many guidance cues, but the causal relationship between these signaling pathways has been unclear. We here report that, for growth cone turning induced by a gradient of myelin-associated glycoprotein (MAG), cAMP acts by modulating MAG-induced Ca2+ signaling. Growth cone repulsion induced by MAG was accompanied by localized Ca2+ signals on the side of the growth cone facing the MAG source, due to Ca2+ release from intracellular stores. Elevating cAMP signaling activity or membrane depolarization enhanced MAG-induced Ca2+ signals and converted growth cone repulsion to attraction. Directly imposing high- or low-amplitude Ca2+ signals with an extracellular gradient of Ca2+ ionophore was sufficient to trigger either attractive or repulsive turning, respectively. Thus, distinct Ca2+ signaling, which can be modulated by cAMP, mediates the bidirectional turning responses induced by MAG.

Animals↗
PubMed2004

Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses.

Activity-induced modification of neuronal connections is essential for the development of the nervous system and may also underlie learning and memory functions of mature brain. Previous studies have shown an increase in dendritic spine density and/or enlargement of spines after the induction of long-term potentiation (LTP). Using two-photon time-lapse imaging of dendritic spines in acute hippocampal slices from neonatal rats, we found that the induction of long-term depression (LTD) by low-frequency stimulation is accompanied by a marked shrinkage of spines, which can be reversed by subsequent high-frequency stimulation that induces LTP. The spine shrinkage requires activation of NMDA receptors and calcineurin, similar to that for LTD. However, spine shrinkage is mediated by cofilin, but not by protein phosphatase 1 (PP1), which is essential for LTD, suggesting that different downstream pathways are involved in spine shrinkage and LTD. This activity-induced spine shrinkage may contribute to activity-dependent elimination of synaptic connections.

Actin Depolymerizing Factors↗
PubMed2004

Spike train timing-dependent associative modification of hippocampal CA3 recurrent synapses by mossy fibers.

In the CA3 region of the hippocampus, extensive recurrent associational/commissural (A/C) connections made by pyramidal cells may function as a network for associative memory storage and recall. We here report that long-term potentiation (LTP) at the A/C synapses can be induced by association of brief spike trains in mossy fibers (MFs) from the dentate gyrus and A/C fibers. This LTP not only required substantial overlap between spike trains in MFs and A/C fibers, but also depended on the temporal order of these spike trains in a manner not predicted by the well-known rule of spike timing-dependent plasticity and requiring activation of type 1 metabotropic glutamate receptors. Importantly, spike trains in a putative single MF input provided effective postsynaptic activity for the induction of LTP at A/C synapses. Thus, the timing of spike trains in individual MFs may code information that is crucial for the associative modification of CA3 recurrent synapses.

2-Amino-5-phosphonovalerate↗
PubMed2004

Bidirectional modification of presynaptic neuronal excitability accompanying spike timing-dependent synaptic plasticity.

Correlated pre- and postsynaptic activity that induces long-term potentiation is known to induce a persistent enhancement of the intrinsic excitability of the presynaptic neuron. Here we report that, associated with the induction of long-term depression in hippocampal cultures and in somatosensory cortical slices, there is also a persistent reduction in the excitability of the presynaptic neuron. This reduction requires postsynaptic Ca(2+) elevation and presynaptic PKA- and PKC-dependent modification of slow-inactivating K(+) channels. The bidirectional changes in neuronal excitability and synaptic efficacy exhibit identical requirements for the temporal order of pre- and postsynaptic activation but reflect two distinct aspects of activity-induced modification of neural circuits.

Animals↗
PubMed2004

Guiding neuronal growth cones using Ca2+ signals.

Pathfinding by growing axons in the developing or regenerating nervous system is guided by gradients of molecular guidance cues. The neuronal growth cone, located at the ends of axons, uses surface receptors to sense these cues and to transduce guidance information to cellular machinery that mediates growth and turning responses. Cytoplasmic Ca2+ signals have key roles in regulating this motility. Global growth cone Ca2+ signals can regulate cytoskeletal elements and membrane dynamics to control elongation, whereas Ca2+ signals localized to one side of the growth cone can cause asymmetric activation of effector enzymes to steer the growth cone. Modulating Ca2+ levels in the growth cone might overcome inhibitory signals that normally prevent regeneration in the central nervous system.

Animals↗
PubMed2004

Reversal and consolidation of activity-induced synaptic modifications.

Persistent activity-induced synaptic modification is generally regarded as the cellular basis for developmental refinement of neuronal connections and for learning and memory. It has long been recognized that synaptic modifications can be reversed by subsequent stimuli. Recent in vivo studies indicate that reversal of synaptic modifications is a natural process that can be triggered by physiological activity. Long-term potentiation (LTP) of hippocampal synapses in adult rats was reversed as rats entered a novel environment. LTP of retinotectal synapses in developing Xenopus was also reversed by subsequent spontaneous activity. Repetitive stimulation with spaced patterns, however, can overcome this reversal, leading to stabilized synaptic modifications. The requirement of spaced stimulus patterns for stable synaptic modifications could ensure appropriate refinement of developing connections.

Animals↗
PubMed2003

ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression.

Extracellular ATP released from axons is known to assist activity-dependent signaling between neurons and Schwann cells in the peripheral nervous system. Here we report that ATP released from astrocytes as a result of neuronal activity can also modulate central synaptic transmission. In cultures of hippocampal neurons, endogenously released ATP tonically suppresses glutamatergic synapses via presynaptic P2Y receptors, an effect that depends on the presence of cocultured astrocytes. Glutamate release accompanying neuronal activity also activates non-NMDA receptors of nearby astrocytes and triggers ATP release from these cells, which in turn causes homo- and heterosynaptic suppression. In CA1 pyramidal neurons of hippocampal slices, a similar synaptic suppression was also produced by adenosine, an immediate degradation product of ATP released by glial cells. Thus, neuron-glia crosstalk may participate in activity-dependent synaptic modulation.

Action Potentials↗
PubMed2003

Brain-derived neurotrophic factor modulation of GABAergic synapses by postsynaptic regulation of chloride transport.

Brain-derived neurotrophic factor (BDNF) potentiates excitatory synapses in a variety of systems by promoting presynaptic transmitter release. The existing evidence indicates that BDNF attenuates inhibitory transmission, but reports differ considerably in their characterization of the effect and proposed mechanisms. We examined the effects of exogenously applied BDNF on EPSCs and IPSCs recorded from functionally identified neurons in dissociated rat hippocampal cultures. When recording from glutamatergic neurons, we found that BDNF exerted differential effects at excitatory versus inhibitory synapses: increasing amplitude of EPSCs but slightly decreasing that of IPSCs. Furthermore, when recording from GABAergic neurons, we found that BDNF increased the IPSC amplitude. That these differential BDNF effects reflect distinct presynaptic and postsynaptic mechanisms was suggested by the BDNF-induced changes in miniature EPSCs and IPSCs. An increased mini-frequency was found at all synapses, indicating elevated presynaptic transmitter secretion; a change in the amplitude of mini-IPSCs was found at GABAergic cells, suggesting postsynaptic modulation of GABA responses. Selective postsynaptic mechanisms were further examined by comparing the effect of BDNF on GABA-induced currents recorded from glutamatergic versus GABAergic cells. For GABAergic but not glutamatergic postsynaptic cells, BDNF induced a shift in the reversal potential (EIPSC) toward more positive levels, hence reducing the inhibitory action of IPSCs. This BDNF-induced effect correlates with the existing level of furosemide-sensitive K+-Cl- transport activity in the postsynaptic cell. Thus, BDNF may decrease the efficacy of inhibitory transmission by acute postsynaptic downregulation of Cl- transport, in addition to its well known presynaptic effect.

Animals↗
PubMed2003

Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl- transporter activity.

Coincident pre- and postsynaptic activation is known to induce long-term modification of glutamatergic synapses. We report here that, in both hippocampal cultures and acute hippocampal slices, repetitive postsynaptic spiking within 20 ms before and after the activation of GABAergic synapses also led to a persistent change in synaptic strength. This synaptic modification required Ca2+ influx through postsynaptic L-type Ca2+ channels and was due to a local decrease in K+-Cl- cotransport activity, effectively reducing the strength of inhibition. Thus, GABAergic synapses can detect and be modified by coincident pre- and postsynaptic spiking, allowing the level of inhibition to be modulated in accordance to the temporal pattern of postsynaptic excitation.

Animals↗