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

Abstract

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.