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Endocannabinoids (eCBs) modulate both excitatory and inhibitory neurotransmission in hippocampus via activation of pre-synaptic cannabinoid receptors. Here, we present a model for cannabinoid mediated short-term depression of excitation (DSE) based on our recently developed model for the equivalent phenomenon of suppressing inhibition (DSI). Furthermore, we derive a simplified formulation of the calcium-mediated endocannabinoid synthesis that underlies short-term modulation of neurotransmission in hippocampus. The simplified model describes cannabinoid-mediated short-term modulation of both hippocampal inhibition and excitation and is ideally suited for large network studies. Moreover, the implementation of the simplified DSI/DSE model provides predictions on how both phenomena are modulated by the magnitude of the pre-synaptic cell's activity. In addition we demonstrate the role of DSE in shaping the post-synaptic cell's firing behaviour qualitatively and quantitatively in dependence on eCB availability and the pre-synaptic cell's activity. Finally, we explore under which conditions the combination of DSI and DSE can temporarily shift the fine balance between excitation and inhibition. This highlights a mechanism by which eCBs might act in a neuro-protective manner during high neural activity.

Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI), a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test 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 elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of endocannabinoids in synaptic transmission as a feedback mechanism both at synaptic and network level.

Sensory gating can be assessed in rodents and humans using an auditory conditioning (C)-test (T) paradigm, with schizophrenic patients exhibiting a loss of gating. Dysregulation of the endocannabinoid system has been proposed to be involved in the pathogenesis of schizophrenia. We studied auditory gating and the effects of the cannabinoid agonist WIN55,212-22 on gating in CA3 and dentate gyrus (DG) of the hippocampus and medial prefrontal cortex (mPFC) in male Lister hooded rats using in vivo electrophysiology. The effects of a single dose of WIN55,212-2 on the N2 local field potential (LFP) test/conditioning amplitude ratios (T/C ratio) and response latencies were examined. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. WIN55,212-2 disrupted auditory gating in all three areas with a significant increase in test amplitudes in the gating rats. A group of non-gating rats demonstrated higher test amplitudes and higher T/C ratios compared to gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A prevented WIN55,212-2 induced disruption of gating. This study demonstrates gated auditory-evoked responses in CA3, DG and mPFC. The mPFC showed an early phase of gating which may later be modulated by CA3 and DG activity. Furthermore, cannabinoid receptor activation disrupted auditory gating in CA3, DG and mPFC, an effect which was prevented by CB1 receptor antagonism. The results further demonstrate the presence of a non-gating rat population which responded differently to cannabinoid agonists.