Endocannabinoid-mediated retrograde modulation of synaptic transmission

• 2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids.
• 2-AG mediates retrograde signals at various types of synapses in the brain.
• 2-AG mediates short- and long-term depression at excitatory and inhibitory synapses.
• Anandamide may mediate a relatively slow, retrograde or non-retrograde signal.
• The endocannabinoid system itself undergoes various plastic changes.

One of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), serves as a retrograde messenger at various types of synapses throughout the brain. Upon postsynaptic activation, 2-AG is released immediately after de novo synthesis, activates presynaptic CB1 cannabinoid receptors, and transiently suppresses neurotransmitter release. When CB1 receptor activation is combined with some other factors such as presynaptic activity, the suppression is converted to a long-lasting form. Whereas 2-AG primarily transmits a rapid, transient, point-to-point retrograde signal, the other major endocannabinoid, anandamide, may function as a relatively slow retrograde or non-retrograde signal or as an agonist of the vanilloid receptor. The endocannabinoid system can be up- or down-regulated by a variety of physiological and environmental factors including stress, which might be clinically important.