Simulations of Implanted Glutamate Sensor Performance in Three Spatial Dimensions and Time Inform Sensor Design and Data Interpretation

Simulations in three dimensions and time provide guidance on implantable, electroenzymatic glutamate sensor design; relative placement in planar sensor arrays; feasibility of sensing synaptic release events; and interpretation of sensor data. Electroenzymatic sensors based on the immobilization of oxidases on microelectrodes have proven valuable for the monitoring of neurotransmitter signaling in deep brain structures; however, the complex extracellular milieu featuring slow diffusive mass transport makes rational sensor design and data interpretation challenging. Simulations show that miniaturization of the disk-shaped device size below a radius of ∼25 μm improves sensitivity, spatial resolution, and the accuracy of glutamate concentration measurements in vivo based on calibration factors determined in vitro. Calculations also show that crosstalk between glutamate sensors in a planar array due to lateral H₂O₂ diffusion is unimportant at micron-scale separation distances, but that the glutamate depletion zone in the vicinity of an individual sensor may limit site spacing to ≳40 μm. Deposition of immobilized glutamate oxidase layers that extend beyond the edge of the underlying microelectrode can improve sensitivity modestly, but H₂O₂ generated by the enzyme at the periphery may not be captured efficiently by the microelectrode, thereby resulting in potentially toxic local H₂O₂ concentrations of ∼25 μM. While simulations predict that detection of glutamate from single-vesicle release events in a synapse would result in current signals that are challenging to detect with conventional equipment, electroenzymatic sensors arranged in planar arrays on biocompatible probes will continue to be a powerful tool for neuroscientists.