Abstract
Cannabinoids have recently received significant attention, due to the important functional role of the endocannabinoid system in modulating brain function. Indeed, increasing public and media interest has focused on the therapeutic potential of cannabinoids in treating a variety of CNS-driven diseases (Ibeas Bih et al., 2015). It is known that cannabinoids primarily produce their biological effects via activation of CB1R and CB2R subtypes (Battista et al., 2012), however in the CNS, the predominant cannabinoid receptor is CB1R. In the hippocampus, varying results have been obtained on the extent and site of cannabinoid-mediated actions on excitatory synaptic transmission (Bajo et al., 2009). Therefore, the aim of this study was to investigate the effects of cannabinoids on excitatory synaptic transmission at different hippocampal CA1 synapses.In this study, standard extracellular recordings were used to examine the effects of different selective CB1R agonists on excitatory synaptic transmission at the temporoammonic (TA) input to CA1 neurons and at the Schaffer Collateral (SC) input to CA1 neurons in rat juvenile hippocampal slices. Our findings indicate that CB1R activation has divergent actions at TA-CA1 and SC-CA1 synapses in juvenile hippocampus. Activation of CB1R, but not CB2R, induces LTP at juvenile TA-CA1 synapses. This represents a novel CB1R and NMDAR-dependent form of LTP that involves PI3K-driven insertion of GluA2-lacking AMPARs into synapses. We also demonstrate that activity-dependent LTP at this synapse requires CB1R activation. Conversely, at juvenile SC-CA1 synapses, CB1R activation induces LTD that is expressed presynaptically, and involves activation of GluN2B-containing NMDARs and stimulation of a PKA-dependent signalling pathway. We also reveal that the non-euphoric phytocannabinoid, cannabidiol (CBD), induces LTP at juvenile TA-CA1 synapses. In a manner similar to CB1R-mediated LTP, CBD-induced LTP has a postsynaptic locus of expression, is NMDAR-dependent, and involves PI3K-dependent trafficking of GluA1 to synapses. CBD also exhibits neuroprotective properties as it prevents the detrimental effects of Aβ1-42; a pathological hallmark of Alzheimer’s disease (AD; Shankar et al., 2008), on synaptic plasticity at TA-CA1 synapses.
Taken together, our overall findings clearly demonstrate that the endocannabinoid system has divergent effects on excitatory synaptic transmission at hippocampal synapses. Consequently, the behavioural effects attributed to cannabinoids cannot be categorized simply as either an impairing or an enhancing effect, especially since several crucial factors influence cannabinoid-mediated actions. Therefore, it will be important to continue to unravel how cannabinoids affect the CNS in health and disease.
| Date of Award | 2021 |
|---|---|
| Original language | English |
| Supervisor | Jenni Harvey (Supervisor) & Andrew Irving (Supervisor) |