A model of endocannabinoid 2-AG-mediated depolarization-induced suppression of inhibition

Depolarization-induced suppression of inhibition (DSI) is known to be mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG). It's calcium-dependent production and subsequent retrograde diffusion from postsynaptic pyramidal cells to presynaptic cannabinoid receptors (CB₁) located on the preterminal axon and the perisynapse of CCK-containing basket cells in the CA1 region of the hippocampus transiently suppresses GABA transmitter release [1, 3]. This endocannabinoid signaling system has many physiological implications for memory-related synaptic plasticity and gamma oscillations; exogenous application of synthetic cannabinoids has a dramatic impact on the functioning of this system, more precisely the loss of synchronized cell assemblies by modification of inhibitory feedback loops in the CA1 region of the hippocampus [4, 5], thus altering outcome of spatial memory-related tasks in animals and learning in humans.

This study uses computational modeling methods to understand the modes of production and action of the endocannabinoid 2-AG in monosynaptically suppressing transmitter release. Using the NEURON simulation environment [2], we developed an isopotential model cell with an L-type Ca²⁺ channel being the sole pathway for Ca²⁺ entry required for synthesis of 2-AG. The observed time courses for 2-AG passive diffusion (between adjacent shell compartments), and uptake and intracellular hydrolysis can be observed with successive depolarizing current pulses delivered by a single-electrode voltage clamp. These changes in concentration levels in the compartment representing the perisynapse and preterminal axon (the CCK-positive basket area covering the pyramidal cell expressing CB₁) are directly proportional to the GABA synaptic depression due to inhibition of presynaptic calcium channels. The amount of CB₁ activation is described by the Langmuir equation and, together with the Ca²⁺ ion cooperativity for transmitter release, affects the synaptic conductance profile described by the solution of two coupled linear ODEs. It is shown that in the model, [Ca²⁺]_i had to rise to 0.1μM in order to sufficiently activate the kinetic model describing the Phospholipase C-Diacylglycerol pathway (PLC-DAG) for 2-AG production [1, 3]. We also show highly simplified dynamics of PLC after stimulation by [Ca²⁺]_i , DAG production, and the spatial gradient in 2-AG across compartments (discretization of Fick's second law for diffusion). Uptake and intracellular hydrolysis is driven by the concentration gradient and the association rate constant for the irreversible reaction hydrolysing 2-AG. The end result observed is the recovery of biexponential postsynaptic conductance time course, which can vary depending on as yet unknown parameter values. The suppression can be effective over a much smaller timescale due to summation of high-frequency inputs by the synapse.