Inhibitory Synapse Growth Is Stimulated In The Vicinity Of Excitatory Synapses

The growth of inhibitory synapses is specifically stimulated in the vicinity of excitatory synapses, researchers at Utrecht University have discovered. The vast majority of synapses are excitatory, which increase the activity of the receiving neuron. Around 10 to 20 percent of synapses have the opposite effect, and are called inhibitory.

“Excitatory and inhibitory synapses create a balance in which the inhibitory synapses play a vital role as ‘directors’ in the brain,”

said Corette Wierenga, co-author of the study.

Inhibitory Synapse Growth

Because neurons pass on information to one another via synapses, good coordination between excitatory and inhibitory signals is essential for information processing.

“We activated individual synapses with a technical trick using laser light. That way, we could repeatedly stimulate four excitatory synapses located very near one another on the dendrite of a single specific neuron. The goal was to cause an excess of local activation in order to study whether it was then compensated with additional inhibition. And that was indeed the case—we observed how a new inhibitory synapse started to grow onto that same dendrite,”

Wierenga said.

Local Dendritic Stimulation Promotes Inhibitory Bouton Growth
Local Dendritic Stimulation Promotes Inhibitory Bouton Growth
Credit: Wierenga, et al. CC-BY

The researchers discovered that under those conditions, the dendrite secretes a chemical signal that stimulates the formation of an inhibitory synapse.

“It’s as if a traffic jam suddenly develops at what is normally a quiet intersection: that’s where the brain needs a new inhibitory synapse to act as a traffic signal,”

explained Wierenga.

Highly Dynamic Process

The formation of dendritic inhibitory synapses is a highly dynamic process, which takes several hours (up to 1 day), and bouton growth is generally the first step in this process (Dobie and Craig, 2011, Villa et al., 2016, Wierenga et al., 2008).

In the hours after initial bouton formation, presynaptic vesicles and postsynaptic gephyrin are slowly recruited (Frias et al., 2019), but not all newly formed boutons will stabilize and form functional inhibitory synapses (Schuemann et al., 2013, Wierenga et al., 2008). The molecular events that take place during this maturation process and the signaling pathways regulating it are only partially known (Flores et al., 2015, Frias et al., 2019, Krueger-Burg et al., 2017, Petrini et al., 2014).

Inhibitory Bouton Growth Is Mediated by Endocannabinoid Signaling
Inhibitory Bouton Growth Is Mediated by Endocannabinoid Signaling
Credit: Wierenga, et al. CC-BY

The current findings identify a triggering mechanism for the formation of new inhibitory boutons at active dendrites, which requires CB1 receptor activation. CB1 receptors are mostly known for mediating synaptic weakening (Monday and Castillo, 2017). The mechanism described here could be related to the atypical endocannabinoid signaling that was recently found to mediate synaptic strengthening (Cui et al., 2016, Wang et al., 2018).

Endocannabinoids

The researchers discovered that the dendrite signals an inhibiting synapse by secreting endocannabinoids. Scientists have long known that neurons produce endocannabinoids – substances that closely resemble the active ingredient in marijuana – but the secretion of these signal chemicals usually results in the weakening of the synapses.

“For the first time, we’ve now proven that endocannabinoids can also stimulate the growth of inhibitory synapses, and we’ve already begun conducting follow-up experiments to study in more detail how that process works,”

Wierenga said.

The work was supported by the Netherlands Organization for Scientific Research, the Foundation for Fundamental Research on Matter, the VICI program, the Research Executive Agency (REA), and by ERCVisionby3DSTIM.

Hai Yin Hu, Dennis L.H. Kruijssen, Cátia P. Frias, Balázs Rózsa, Casper C. Hoogenraad, Corette J. Wierenga
Endocannabinoid Signaling Mediates Local Dendritic Coordination between Excitatory and Inhibitory Synapses
Cell Reports; Volume 27, Issue 3, p666-675.E5, April 16, 2019

Top Image: Elmer Guzman


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