Endocannabinoids regulate mAChR-evoked theta rhythm IPSCs in hippocampus

Abstract

Exogenous cannabinoids can affect behaviorally relevant neuronal oscillations, but there is little evidence that endogenous cannabinoids (endocannabinoids, eCBs) can affect them, although it is unknown whether eCBs were generated during oscillations investigated in previous studies. In rat hippocampal slices, muscarinic receptor (mAChR) agonists stimulate the occurrence of persistent, rhythmic inhibitory post-synaptic currents (IPSC) activity and mobilize eCBs. We tested the hypothesis that mAChR-induced IPSCs would be modulated by concomitantly produced eCBs. With ionotropic glutamate receptors inhibited, mAChR agonist application triggered eCB-sensitive IPSCs that were enhanced in amplitude and frequency when a cannabinoid receptor antagonist was also present. There was also a highly significant increase in IPSC spectral power in the theta-frequency range. The data show that eCBs released by mAChRs modulate rhythmic IPSCs, and suggest that eCBs are candidate regulators of neuronal oscillations associated with eCB production in vivo.\n\nSignificance statementEndocannabinoids (eCB) are ubiquitous and powerful modulators of neuronal activity, acting in the brain mainly via cannabinoid receptors (CB1Rs) on presynaptic nerve terminals, and inhibiting neurotransmitter release. Numerous neurotransmitters, including acetylcholine (ACh), stimulate eCB release. Behaviorally important neuronal oscillations can be suppressed by exogenous cannabinoids, suggesting that eCBs could regulate oscillations normally. Such regulation, if it occurred, would represent an important new dimension of eCB actions, but to date there is little evidence that eCBs do affect neuronal oscillations. Given the enrichment of eCBs and CB1Rs in brain regions whose behavioral roles depend on neuronal oscillations, including the hippocampus, it is important to understand whether, or how, the eCBs affect rhythms.