Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction

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A gradient of bone morphogenetic proteins (BMPs) along the dorsoventral axis of the spinal cord is necessary for the specification of dorsal neurons. Concurrently, a gradient of calcium-mediated electrical activity is present in the developing spinal cord but in an opposing ventrodorsal direction. Whether BMPs and electrical activity interact in embryonic spinal neurons remains unknown. We show that BMP decreases electrical activity by enhancing p38 MAPK-mediated negative modulation of voltage-gated sodium channels. In turn, electrical activity affects the phosphorylation status and nuclear level of activated Smads, the canonical components of BMP signaling. This interaction between calcium spike activity and BMP signaling regulates the specification of the dorsal commissural spinal neuron phenotype. The present study identifies an unexpected interplay between BMPs and electrical activity that is critical for decoding the morphogen gradient during spinal neuron differentiation.calcium signaling | spinal interneuron | mitogen-activated protein kinase | noggin | activity-dependent neuronal specification N ervous system function relies on connections among specialized cells that acquire their distinctive identity during embryonic development. Specialization of neurons originates with the specification of neural progenitors driven by secreted factors present as gradients along the main axes of the developing nervous system. Prototypical of these molecules are bone morphogenetic proteins (BMPs), members of the TGF-β superfamily (1). Among the numerous BMPs, Bmp2, Bmp4, Bmp7, growth differentiation factor 7 (Gdf7), activin, and dorsalin are expressed in the roof plate during neural tube development (1-3). In vitro and in vivo experiments in various organisms have shown that the dorsoventral BMP gradient (4, 5) is essential for specification of dorsal sensory neurons and interneurons, such as the commissural interneurons (1, 3, 6). The mechanisms by which BMP gradient is deciphered remain unclear.BMP ligands form a homomeric or heteromeric complex that binds to two types of transmembrane serine-threonine kinase receptor, the type I (BMPRIA and BMPRIB) and type II (BMPRII) receptors (7). Following BMP binding, the type II receptor phosphorylates the type I receptor (8). This process leads to the Cterminal phosphorylation of the pathway-restricted Smads (RSmads, Smads1, -5, or -8), which are then released from the receptor and recruit the common mediator Smad (Co-Smad, Smad4) into a complex. This complex migrates into the nucleus and activates the transcription of specific target genes (9, 10), constituting the canonical BMP signaling pathway. BMP can also recruit the MAPK pathway through receptor-mediated phosphorylation of Tak1, leading to the activation of p38 MAPK (11,12). BMP stimulation has also been shown to activate the Erk1/2 and LIM kinases in certain cell types (13,14). The role of BMP noncanonical pathways during dorsoventral spinal phenotype differentiation and whether different signaling cascades function i...

Section: Methodsmentioning

confidence: 99%

“…In vivo drug delivery was performed as previously described (20,21,49). Agarose beads (80 μm; BioRad) were loaded for at least 1 h with the indicated agents.…”

Section: Methodsmentioning

confidence: 99%

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Interplay between electrical activity and bone morphogenetic protein signaling regulates spinal neuron differentiation

Swapna

Borodinsky

2012

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“…Vertebrate skeletal muscle expresses five classes of neurotransmitter receptors at early developmental stages, four of which are eliminated during the achievement of the mature cholinergic phenotype. In this model, NMDA-and AMPAreceptor expression increases when activity is suppressed and decreases when activity is enhanced (3). Interestingly, under experimental glutamatergic innervation, the rat neuromuscular junction switches from cholinergic-to glutamatergic-type synapse (4).…”

mentioning

confidence: 99%

Transmitter-receptor mismatch in GABAergic synapses in the absence of activity

Cesa

Morando

Strata

2008

Competition among different axons to reach the somatodendritic region of the target neuron is an important event during development to achieve the final architecture typical of the mature brain. Trasmitter-receptor matching is a critical step for the signaling between neurons. In the cerebellar cortex, there is a persistent competition between the two glutamatergic inputs, the parallel fibers and the climbing fibers, for the innervation of the Purkinje cells. The activity of the latter input is necessary to maintain its own synaptic contacts on the proximal dendritic domain and to confine the parallel fibers in the distal one. Here, we show that climbing fiber activity also limits the distribution of the GABAergic input in the proximal domain. In addition, blocking the activity by tetrodotoxin infusion in Wistar rat cerebellum, a synapse made by GABAergic terminals onto the recently formed Purkinje cell spines appear in the proximal dendrites. The density of GABAergic terminals is increased, and unexpected double symmetric/asymmetric postsynaptic densities add to the typical symmetric phenotype of the GABAergic shaft synapses. Moreover, glutamate receptors appear in these ectopic synapses even in the absence of glutamate transmitter inside the presynaptic terminal and close to GABA receptors. These results suggest that the Purkinje cell has an intrinsic tendency to develop postsynaptic assemblies of excitatory types, including glutamate receptors, over the entire dendritic territory. GABA receptors are induced in these assemblies when contacted by GABAergic terminals, thus leading to the formation of hybrid synapses.cerebellum ͉ GABA receptor ͉ spinogenesis ͉ synaptic plasticity

“…Because short-term plasticity often involves only one component of the synapse (22)(23)(24), the question arises: How does information about synaptic plasticity spread from its site of origin to recruit the other component of the synapse? Studies of synaptic growth during development have revealed a fairly elaborate program of pre-and postsynaptic changes involving a variety of orthograde and retrograde messengers (25), including activity-dependent or spontaneous release of the transmitter itself (26)(27)(28)(29)(30). We have now investigated the possible role of spontaneous transmitter release from the presynaptic neuron as an orthograde signal for recruiting the postsynaptic mechanisms of long-term plasticity.…”

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confidence: 99%

Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation inAplysia

Jin

Puthanveettil

Udo

et al. 2012

Long-term plasticity can differ from short-term in recruiting the growth of new synaptic connections, a process that requires the participation of both the presynaptic and postsynaptic components of the synapse. How does information about synaptic plasticity spread from its site of origin to recruit the other component? The answer to this question is not known in most systems. We have investigated the possible role of spontaneous transmitter release as such a transsynaptic signal. Until recently, relatively little has been known about the functions of spontaneous release. In this paper, we report that spontaneous release is critical for the induction of a learning-related form of synaptic plasticity, long-term facilitation in Aplysia. In addition, we have found that this signaling is engaged quite early, during an intermediate-term stage that is the first stage to involve postsynaptic as well as presynaptic molecular mechanisms. In a companion paper, we show that spontaneous release from the presynaptic neuron acts as an orthograde signal to recruit the postsynaptic mechanisms of intermediate-term facilitation and initiates a cascade that can culminate in synaptic growth with additional stimulation during long-term facilitation. Spontaneous release could make a similar contribution to learning-related synaptic plasticity in mammals.serotonin | cell culture | miniature excitatory postsynaptic current | octopamine | botulinum toxin S pontaneous transmitter release was discovered 60 y ago by Fatt and Katz (1), who found that it represents the quantal unit of transmitter release evoked by a presynaptic action potential. However, until recently, relatively little has been known about other possible functions of spontaneous release. In the last few years, we have learned that spontaneous release can contribute to postsynaptic firing (2, 3), regulation of postsynaptic kinase pathways (4), and maintenance of postsynaptic dendritic spines and receptors (5, 6). Spontaneous release has also been found to contribute to some cases of homeostatic scaling of synaptic strength (7-14). Here we report a role of spontaneous transmitter release in the induction of a learning-related form of synaptic plasticity, longterm facilitation produced by serotonin (5HT) in Aplysia.Long-term plasticity can differ from short-term in recruiting the growth of new synaptic connections, a process that requires the participation of both the presynaptic and postsynaptic components of the synapse (15-21). Because short-term plasticity often involves only one component of the synapse (22-24), the question arises: How does information about synaptic plasticity spread from its site of origin to recruit the other component of the synapse? Studies of synaptic growth during development have revealed a fairly elaborate program of pre-and postsynaptic changes involving a variety of orthograde and retrograde messengers (25), including activity-dependent or spontaneous release of the transmitter itself (26-30). We have now investigated the possible role of spo...