Molecular mechanisms determining the polarised synaptic distribution and molecular function of the retrograde endocannabinoid signalling system

The endocannabinoid system (ECS) acts as a negative feedback mechanism to suppress excitatory and inhibitory synaptic transmission. This is critically important for a wide range of brain functions including appetite, pain, and cognition.

Moreover, ECS dysfunction is implicated in multiple neuropathologies, and there is increasing scientific and public interest in drugs that target the ECS, including medical marijuana.

The molecular organisation of the ECS is highly unusual because, in reverse to other neurotransmitter systems, endocannabinoids are released from the postsynaptic membrane to activate receptors at the presynaptic membrane.

Despite its importance, remarkably little is known about how the enzymes and receptors essential for ECS ‘backwards’ transmission are targeted to, and retained at, opposing sides of the synapse.

Focusing on the primary cannabinoid receptor CB1R and the major endocannabinoid synthesising enzyme diacylglycerol lipase α (DAGLα) as prototypic examples, we will investigate the protein interactions and pathways that determine the architecture and organisation of the ECS. Our goal is to define how the differentially polarised trafficking of ECS components to synapses is orchestrated.

This mechanistic knowledge of the ECS will advance understanding of neuronal protein polarisation and inform the design of future strategies to modulate ECS signalling for therapeutic benefit.