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Modelling Of Zinc Movements In The Synaptic Cleft Of Hippocampal Ca3 Area

Authors: Quinta Ferreira M.E. , Sampaio dos Aidos F.D.S., Dionisio J.C., Quinta Ferreira R.M., Matias C.M.

Ref.: 8th FENS (Federation of European Neuroscience Societies) Forum of Neuroscience, 10th to 14th de July 2012, Barcelona, Spain. 6 (2012)

Abstract: Zinc has an important role in multiple aspects of cellular activity and is one of the most abundant transition metals in the CNS. In particular the zinc-rich mossy fiber terminals from hippocampal CA3 area, release large amounts of zinc from glutamatergic synaptic vesicles. At these synapses, characterized by one of the highest concentrations of zinc in the brain, it is considered that zinc is co-released with glutamate in a calcium-dependent way, following both low and high levels of stimulation. Upon release into the synaptic cleft, zinc can act on specific membrane and extracellular zinc-binding proteins including glutamate receptors, ionic channels, transporters and chelating agents. Besides having an inhibitory or excitatory action, zinc may also permeate ionotropic glutamate receptors and voltage dependent calcium channels (VDCCs). The objective of this work is to build a computer model to describe zinc mobilization in the synaptic cleft of the mossy fiber synapses, following electrical stimulation of the mossy fiber pathway. This model considers zinc changes in the cleft associated with transmitter release, on the basis of existing information about zinc release, transport systems and zinc buffers. Different types of glutamate receptors and VDCCs, which can be modulated by zinc, are also taken into account. The simulations allow the evaluation of relative dynamic properties of zinc-binding to sites present in post- and presynaptic membranes and in the synaptic cleft, following stimuli-evoked zinc release. For this purpose, concentrations and rate constants obtained from the literature are used in a numerical model solved by a 4th order Runge-Kutta method, to simulate induced fast zinc movements in the synaptic cleft. The results allow the comparison of the time courses and relative contributions of various zinc processes involved specially in fast zinc-mediated inhibition or enhancement and in zinc clearance.