Behaviorally relevant endocannabinoid action in hippocampus: dependence on temporal summation of multiple inputs

Endocannabinoids have been shown to mediate depolarization-induced suppression of GABAergic inhibition (DSI), possibly via release and retrograde diffusion following moderate to severe depolarization of hippocampal pyramidal neurons. However, it is not clear how hippocampal neurons, which have relatively low firing rates in vivo, achieve the degree of depolarization required to release endocannabinoids. Here it is demonstrated that DSI is not dependent on the occurrence of action potentials in the postsynaptic neuron, but is mediated by depolarization-induced calcium entry via voltage-controlled calcium channels (VCCs). The optimal level of calcium entry, and subsequent DSI, are directly related to the frequency of depolarizing pulses, which differs between immature and adult hippocampus. However, it is shown via modeled spike train inputs that the frequency dependence of DSI is overcome if two or more convergent spike trains from different neurons with normal in vivo firing rates converge and overlap in time. In these modeled circumstances, endocannabinoid-mediated DSI occurs most often when converging synaptic inputs from multiple neurons fire in synchrony to allow temporal summation of local membrane events in postsynaptic cells to exceed threshold for calcium entry. It is therefore possible that such suppression of inhibition would only occur during the time that recipient hippocampal neurons receive multiple coincident excitatory synaptic inputs.