ASSESSMENT OF FREQUENCY-DEPENDENT ALTERATIONS IN THE LEVEL OF EXTRACELLULAR CA2+ IN THE SYNAPTIC CLEFT

The synaptic cleft may be represented as a very thin disk of extracell ular fluid. It is possible that at high stimulation frequencies the in terval between pulses would be insufficient for diffusion of Ca2+ from the periphery of the cleft to replace extracellular Ca2+ depleted at the center of the cleft as a result of activation of postsynaptic, Ca2 +-permeable channels. Computer modeling was employed to assess the imp act of activation of glutamate receptor channels (GRCs) in the postsyn aptic membrane on the level of extracellular Ca2+ within the synaptic cleft. The model includes calcium influx from the synaptic cleft into the postsynaptic compartment through GRC and calcium efflux through ca lcium pumps and Na/Ca exchangers. Concentrations of extracellular Ca2 inside the cleft are estimated by using a compartmental model incorpo rating flux across the postsynaptic membrane and radial diffusion from the edges of the cleft. The simulations suggest that substantial extr acellular Ca2+ depletion can occur in the clefts during activation of GRCs, particularly at high stimulation frequencies used to induce long -term potentiation (LTP). Only minimal transitory changes in extracell ular Ca2+ are observed at low frequencies. These frequency-dependent a lterations in extracellular Ca2+ dynamics are a direct reflection of t he activity of GRCs and could be involved in the modulation of presyna ptic function via a retrograde messenger mechanism, if there are extra cellular Ca2+ sensors on the presynaptic membranes. The recently clone d extracellular Ca2+-sensing receptors that are known to be present in nerve terminals in hippocampus and other areas of the brain could pot entially play such a role.