Synaptic Compensation Driven by Action Potential-Independent Vesicle Release
Material below summarizes the article Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo, published on July 6, 2016, in JNeurosci and authored by Miguel Angel Garcia-Bereguiain, Carlos Gonzalez-Islas, Casie Lindsly, and Peter Wenner.
Neural networks must balance excitation and inhibition throughout development and maturity. Many neural disorders are associated with an imbalance of excitation and inhibition, including spasticity, seizure activity, and several neurodevelopmental disorders.
A constellation of mechanisms are thought to maintain the normal excitatory-inhibitory balance. When neural activity is perturbed, compensatory homeostatic mechanisms are engaged. These include changes in intrinsic membrane excitability — for example, by changing the expression or activation state of K+ channels — or changes in excitatory and inhibitory synaptic strength.
The best studied form of homeostatic plasticity is called synaptic scaling, in which all of the synaptic inputs to a cell are scaled by a numerical factor — for example, all inputs become twice as strong. It is thought that scaling acts to maintain spiking activity levels, and that it is triggered by changes in spiking activity.
We had previously shown that reducing neural network activity in the living chick embryo caused a scaling up of excitatory synaptic inputs in spinal motoneurons. In that study, we infused a drug that blocks action potentials into the egg for two days in the middle of the embryonic period. We believed that scaling up was triggered by reduced spiking in the system and represented a compensation to recover the spinal network activity that drove embryonic movements.
We also demonstrated that the scaling had likely been triggered by a reduction in GABAA receptor activation, which is excitatory in the embryo, but then becomes the main inhibitory transmitter in maturity. Injecting GABAergic antagonists into the egg abolished embryonic movements which then recovered 12 hours later. Although the embryonic movements were recovered and GABAergic blockade triggered the plasticity, we discovered that scaling had not yet been expressed at the time the recovery had been achieved. This was our first indication that scaling and spiking might not be as tightly associated as we believed.
We suspected that in our initial study blocking action potentials (AP) reduced network activity and thus significantly reduced GABA release, thereby decreasing GABA receptor activation, which triggered upscaling.
In the current study, we sought to test whether AP-dependent release of GABA that occurred during bouts of network activity was critical to the scaling process.
We altered AP-dependent release using nicotinic modulators, which altered GABA release presynaptically. When we decreased GABA release for two days we observed upscaling. When we increased GABA release we saw downscaling (making all synaptic inputs weaker by a numerical factor).
However, we also noticed that the nicotinic modulators produced a strong change in spontaneous GABA release that did not require action potentials. We wondered whether this spontaneous release could also contribute to scaling.
So, we blocked spiking activity, which would normally cause an upscaling, and co-treated with a nicotinic modulator that increased spontaneous GABA release that by itself caused downscaling. We expected that we might observe something in between upscaling and downscaling but were surprised to observe a downscaling that was no different than increasing GABA release without spike blockade.
In other words, upscaling triggered by spike blockade was converted to downscaling by simply increasing spontaneous GABA release. While spontaneous release seemed to be key to the scaling process, network spiking did not. The downscaling that was triggered by increasing GABA release was no different whether network activity was elevated or blocked.
Therefore, the levels of activity were quite different in these two conditions, and yet both triggered a similar level of downscaling. This argued against the idea that some aspect of network activity triggered scaling, whether it be spiking during these bursts, associated large calcium transients, or even GABAA receptor activation that occurred during the bouts of activity.
We then repeated these experiments with a drug that more specifically influenced spontaneous GABA release and again saw a profound scaling.
These results were surprising and suggested that fairly mild perturbations in GABA receptor activation (spontaneous release alone) produced the full range of scaling, while network activity had little effect on the expression of this form of homeostatic plasticity.
Together with previous work in the chick embryo, we find that scaling does not appear to act for the homeostatic maintenance of network spiking, and it is not directly triggered by spiking. Rather, scaling likely acts to maintain synaptic strength.
By understanding the triggers for this form of homeostatic plasticity, we can begin to determine if the same pathways are activated following neural injury or in disease in future studies. This will start to provide an understanding of why damaged, diseased, or drug-exposed neural networks fail to function properly, whether it is a failure to compensate or an inappropriate trigger of a compensatory mechanism.
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Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo. Miguel Angel Garcia-Bereguiain, Carlos Gonzalez-Islas, Casie Lindsly and Peter Wenner. JNeurosci Jul 2016, 36 (27) 7268-7282; DOI: http://dx.doi.org/10.1523/JNEUROSCI.4066-15.2016.
