A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition

Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. Theplasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basisof learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespreadaction on brain function through modulation of synap–tic transmission and plasticity. Recent experimental studies havecharacterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brainregions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning andmemory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level andinvestigate how this signalling mediates depolarisation induced suppression of inhibition (DSI), a prominent form of shorttermsynaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the keycharacteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematicaldescription of the major signalling molecules and cascades involved. More specifically, this model serves as a framework totest hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked.The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicitDSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firingrate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigateexperimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as astepping stone for future deciphering of the role of endocannabinoids in synaptic transmission as a feedback mechanismboth at synaptic and network level