Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo

García-Bereguiaín, Miguel Angel; González-Islas, Carlos; Lindsly, Casie; Wenner, Peter

doi:10.1523/jneurosci.4066-15.2016

Cited by 24 publications

(19 citation statements)

References 59 publications

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“…It is possible that activity levels in our culture and slice models are altered transiently after initial loss of protein and normalize before the time of assessment, but another intriguing hypothesis is that the signalling cascades driven by spontaneous neurotransmission and normally associated with homeostasis are, in fact, separable from signalling cascades driven by activity. Supporting this view, a recent study showed that chick embryonic spinal cord neurons appear to produce scaling in response to changes in spontaneous neurotransmission after, and sometimes in the absence of, homeostatic changes in evoked neurotransmission 46 . Although vti1a- and VAMP-dependent neurotransmission triggers signalling cascades known to be involved in homeostatic processes 19 and, therefore, may physiologically participate in activity homeostasis, it is possible that these forms of neurotransmission operate with some degree of independence 9 .…”

Section: Discussionmentioning

confidence: 90%

Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy

et al. 2017

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Recent studies suggest that stimulus-evoked and spontaneous neurotransmitter release processes are mechanistically distinct. Here we targeted the non-canonical synaptic vesicle SNAREs Vps10p-tail-interactor-1a (vti1a) and vesicle-associated membrane protein 7 (VAMP7) to specifically inhibit spontaneous release events and probe whether these events signal independently of evoked release to the postsynaptic neuron. We found that loss of vti1a and VAMP7 impairs spontaneous high-frequency glutamate release and augments unitary event amplitudes by reducing postsynaptic eukaryotic elongation factor 2 kinase (eEF2K) activity subsequent to the reduction in N-methyl-D-aspartate receptor (NMDAR) activity. Presynaptic, but not postsynaptic, loss of vti1a and VAMP7 occludes NMDAR antagonist-induced synaptic potentiation in an intact circuit, confirming the role of these vesicular SNAREs in setting synaptic strength. Collectively, these results demonstrate that spontaneous neurotransmission signals independently of stimulus-evoked release and highlight its role as a key regulator of postsynaptic efficacy.

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Section: Discussionmentioning

confidence: 90%

Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy

et al. 2017

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“…Following GABA A R blockade, compensatory changes in synaptic strength (scaling) were not observed until 48 h, but voltage-gated conductance changes were triggered by 12 h (Wilhelm and Wenner, 2008;Wilhelm et al, 2009). It has been recently reported that simply reducing GABA A R activation due to spontaneous miniature release of GABA vesicles (spontaneous GABAergic transmission) was sufficient to trigger upscaling (Garcia-Bereguiain et al, 2016). We were able to do this by taking advantage of our observation that manipulating nicotinic receptor activation altered spontaneous GABAergic release (Gonzalez-Islas et al, 2016).…”

Section: The Trigger For Changes In Rmp Was Distinct From the Homeostmentioning

confidence: 80%

Homeostatic Recovery of Embryonic Spinal Activity Initiated by Compensatory Changes in Resting Membrane Potential

González-Islas

García-Bereguiaín

Wenner

2020

eNeuro

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When baseline activity in a neuronal network is modified by external challenges, a set of mechanisms is prompted to homeostatically restore activity levels. These homeostatic mechanisms are thought to be profoundly important in the maturation of the network. It has been shown that blockade of either excitatory GABAergic or glutamatergic transmission in the living chick embryo transiently blocks the movements generated by spontaneous network activity (SNA) in the spinal cord. However, the embryonic movements then begin to recover by 2 h and are completely restored by 12 h of persistent receptor blockade. It remains unclear what mechanisms mediate this early recovery (first hours) after neurotransmitter blockade, or even if the same mechanisms are triggered following GABAergic and glutamatergic antagonists. Here we find two distinct mechanisms that could underlie this homeostatic recovery. First, we see a highly robust compensatory mechanism observed shortly after neurotransmitter receptor blockade. In the first 2 h of GABAergic or glutamatergic blockade in vitro, there was a clear depolarization of resting membrane potential (RMP) in both motoneurons and interneurons. These changes reduced threshold current and were observed in the continued presence of the antagonist. Therefore, it appears that fast changes in RMP represent a key fast homeostatic mechanism for the maintenance of network activity. Second, we see a less consistent compensatory change in the absolute threshold voltage in the first several hours of in vitro and in vivo neurotransmitter blockade. These mechanisms likely contribute to the homeostatic recovery of embryonic movements following neurotransmitter blockade.

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“…Assuming the increase in episode frequency as inhibitory synapses become even more inhibitory can be observed, what possible role could it have? Many of the developmental changes that occur during network maturation, including the change in reversal potential of GABAergic synapses (Ganguly et al, 2001 ; Garcia-Bereguiain et al, 2016 ) are dependent on spontaneous activity, which recruits large parts of the network in a coordinated manner. If spontaneous activity stopped too early, this could prevent some of the activity-dependent changes to occur.…”

Section: Discussionmentioning

confidence: 99%

The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems

Blanco

Bertram

Tabak

2017

Front. Comput. Neurosci.

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Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the “intermediate neurons.” We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes that occur during development that may be observable even in actual neural systems where these changes are convoluted with changes in synaptic connectivity and intrinsic neural plasticity.

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Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo

Cited by 24 publications

References 59 publications

Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy

Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy

Homeostatic Recovery of Embryonic Spinal Activity Initiated by Compensatory Changes in Resting Membrane Potential

The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems

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