Endocannabinoid Release Timing Controls Synaptic Connection Changes

Learning and memory depend on processes that alter the connections – or synapses – between neurons in the brain.

For example, molecules called endocannabinoids can alter synapses to decrease the influence that one neuron has on another neuron’s activity. This “synaptic depression” is an important mechanism through which the brain can adapt to an experience.

However, recent research also suggests that endocannabinoids might also increase the influence one neuron has on another neuron’s activity by strengthening the synaptic connection between neurons. This opposite process is known as synaptic potentiation, and is also important for learning from experience.

But how do endocannabinoids manage to produce opposing effects?

Paired-activity Dependent

Using a combination of electrophysiological recording experiments and mathematical modeling, the University Pierre et Marie Curie’s Yihui Cui, and colleagues, have now deciphered the molecular mechanisms that govern the action of endocannabinoids at key synapses in rat brain slices. This revealed that both the levels and timing of endocannabinoid release control changes in the strength of the synaptic connections.

spike timing dependance ecb

Spike-timing dependence in the endocannabinoid-signaling part of the model.
Credit: Cui et al. CC-BY

Electrical stimulations that produced moderate amounts of endocannabinoids over a prolonged period led to synaptic depression.

However, stimulation that produced short but large endocannabinoid peaks caused synaptic potentiation. The enzymes that control endocannabinoid levels thus play a crucial role in determining whether a given stimulation leads to the strengthening or weakening of a synaptic connection.

Abnormal Dopamine Production

In the type of synapses studied by Cui et al., changes to synaptic strength also depend on another chemical called dopamine. Abnormal dopamine production is implicated in a number of disorders, including Parkinson’s disease and addiction.

Future work will therefore investigate how dopamine controls endocannabinoid-dependent changes to the strength of synapses.

Funding came from the Agence Nationale de la Recherche.

Yihui Cui, Ilya Prokin, Hao Xu, Bruno Delord, Stephane Genet, Laurent Venance, Hugues Berry
Endocannabinoid dynamics gate spike-timing dependent depression and potentiation
eLife 2016;5:e13185 DOI: 10.7554/eLife.13185

© 2016, Cui et al. Republished via Creative Commons Attribution License. Top Image: Cui et al. CC-BY