Region- and activity-dependent regulation of extracellular glutamate in the brain

Abstract

The rapid removal of synaptically-released glutamate is essential to maintain fast excitatory chemical neurotransmission and to prevent NMDA receptors mediated synaptic plasticity impairments and cell death. Here, we used the rapid extracellular fluorescent glutamate sensor, iGluSnFR (intensity-based glutamate sensing fluorescent reporter), and high-speed imaging to quantify relative differences in glutamate clearance rates over a wide range of presynaptic activity in situ in the hippocampus, cortex, striatum and cerebellum of male C57/BL6NCrl mice. We found that the hippocampus was significantly more efficient at clearing synaptically-released glutamate. We also found that pharmacological inhibition of GLT-1, the brain’s most abundant glutamate transporter, slowed clearance rates to only ~ 20-25% of the effect induced by non-selective transporter blockade. In all, our data reveal clear regional differences in glutamate dynamics following neural activity and suggest that non-GLT-1 transporters can make a large contribution to the rate of glutamate clearance when GLT-1 is dysfunctional.