Depolarization-induced Suppression of Inhibition - DSI Mediation By Endocannabinoids

DSI Mediation By Endocannabinoids

DSI was thought to be due to a reduction in pre-synaptic neurotransmitter release for 2 reasons. 1) The magnitudes of spontaneously evoked inhibitory post-synaptic currents (IPSCs), caused by the release of a single pre-synaptic vesicle filled with GABA, remained unchanged and 2) The cellular responses to exogenously applied GABA remained the same. These observations suggested that no changes occurred in the post-synaptic cell to change its responsiveness to GABA during DSI. Somehow, DSI appeared to be mediated by a retrograde synaptic messenger whose synthesis or release was stimulated by the depolarization of the target cell. This messenger then diffused "backwards" to the pre-synaptic cell, where it caused a reduction in neurotransmitter release.

The chemical messengers presumed to be responsible for mediating DSI was discovered by three separate groups in 2001. Wilson & Nicoll (2001) published their work in the prestigious journal, Nature, while the other two groups, Kreitzer & Regehr (2001) and Ohno-Shosaku et al. (2001), published in the same issue of another reputable journal, Neuron. All three demonstrated heavy involvement of the CB1 cannabinoid receptor in DSI, suggesting that the endocannabinoids were the brain's mediators of DSI. They showed that cannabinoid receptor agonists, drugs that mimic the actions of endocannabinoids or THC, could evoke the same reduction in inhibitory currents caused by DSI. They also demonstrated that DSI could be prevented by cannabinoid receptor antagonists, drugs that block the actions of cannabinoid compounds.

Other lines of evidence support the role of the CB1 receptor in DSI. This receptor is distributed very widely throughout the brain, covering all areas where DSI has been observed (Herkenham et al. 1990). The CB1 receptor also appears to be expressed mainly on GABA-ergic pre-synaptic terminals, making it an excellent candidate for mediating DSI (Matyas et al. 2006, Katona et al. 1999). In 2005, other groups began to demonstrate the involvement of the CB1 receptor in DSI in other regions of the brain (Jo et al. 2005, Bodor et al. 2005). Lastly, DSI research was finally applied to mice that had the CB1 receptor genetically "knocked-out". So far, these knock-out mice are not known to exhibit DSI in any regions of the brain, suggesting that the CB1 receptor is the crucial mediator for DSI (Kreitzer & Regehr 2001a, Ohno-Shosaku et al. 2002).

The discovery that DSI is mediated by endocannabinoids finally explained why both the CB1 receptor and the endocannabinoids are both so widely distributed in the brain. DSI is a very common form of short-term plasticity and thus needs to be mediated by a commonly found neurotransmitter. The use of endocannabinoids such as anandamide and 2-arachidonoyl glycerol in this method of signalling is quite logical, since both molecules can be synthesized relatively easily from lipids in the plasma membrane, a fundamental constituent of all cells. DSI is therefore the primary cortical process mediated by the endocannabinoids, and may contribute to many forms of cortical plasticity and synaptic strengthening, such as in long-term potentiation (Carlson et al. 2002).