6533b7d0fe1ef96bd125a18e

RESEARCH PRODUCT

Plasticity of mouse enteric synapses mediated through endocannabinoid and purinergic signaling

subject

description

The myenteric and submucosal plexuses of the enteric nervous system (ENS) exist as interconnected integrative nerve networks within the wall of the gastrointestinal (GI) tract. Activity of the ENS is responsible for the control of the digestive and protective functions of the gut.1 Synaptic transmission between enteric neurons propagates information from intrinsic afferent neurons to interneurons, and then from interneurons to motor neurons that control final effectors such as smooth muscle and the secretory epithelium. Acetylcholine (ACh) is the major excitatory neurotransmitter in the myenteric plexus, acting on nicotinic receptors at synapses between neurons and on muscarinic receptors at neuromuscular junctions.1,2 Unlike the central nervous system (CNS), fast inhibitory neurotransmission is not commonly observed in the myenteric plexus. Norepinephrine released from extrinsic sympathetic terminals generates inhibitory post-synaptic potentials of an intermediate duration in the guinea pig. But the role of norepinephrine in regulating the moment-to-moment function of the GI tract is unclear, since under physiological conditions sympathetic denervation has little effect.3 Thus, other mechanisms are likely to exist that could more specifically control synaptic strength in the ENS, through the graded control of ACh release from the presynaptic neuron. In the CNS, the discovery of retrograde endocannabinoid signalling provided an explanation for some forms of postsynaptic activity-dependent changes in presynaptic neurotransmitter release.4,5 Presynaptic activation of the cannabinoid (CB)1 receptor causes both transient and sustained inhibition of neurotransmitter release, allowing for several forms of synaptic plasticity.4,6,7 Furthermore, CB1 receptor-mediated plasticity at the synapse can itself be regulated, a phenomenon known as metaplasticity.8,9 If a similar system is functioning at enteric synapses, then activity-dependent endocannabinoid signalling could exert homeostatic inhibitory control of excitatory neurotransmission in the ENS. CB1 receptors are expressed in the ENS, and in this system, exogenous CB1 receptor agonists inhibit ACh release and reduce the amplitude of fast excitatory post-synaptic potentials (fast EPSPs).10–12 The key elements of the endocannabinoid signalling system are present in the ENS, including receptors13–15 and putative transporters,16 as well as the enzymes responsible for the synthesis and degradation of endocannabinoids.13,17,18 Through the use of drugs that target individual components of this system it is apparent that cannabinoid signalling influences motor and other gut functions,13 but its role in enteric neurotransmission remains to be determined. In the gut, there also appears to be a basal level of endocannabinoid tone.12,13,19 We tested the hypothesis that enteric CB1 receptors provide inhibitory control of excitatory neurotransmission in the ENS. Our data support this hypothesis, and we have also discovered a new form of metaplasticity in the ENS, that has not been previously been reported in the peripheral or central nervous system.