Synaptic glutamate spillover increases NMDA receptor reliability at the cerebellar glomerulus.

Glutamate spillover in the mossy fiber to granule cell cerebellar glomeruli has been hypothesized to increase neurotransmission reliability. In this study, we evaluate this hypothesis using an experimentally based quantitative model of glutamate spillover on the N-methyl-d-aspartate receptors (NMDA-Rs) at the cerebellar glomerulus. The transient and steady-state responses of NMDA-Rs were examined over a physiological range of firing rates. Examined cases included direct glutamate release activation, glutamate spillover activation, and a combination of direct and spillover activation. Our results illustrate that the effects of spillover alone are equivalent to direct release and, notably, combined spillover and direct release effects on NMDA-Rs are not additive. Our results show that spillover does in fact provide a high degree of reliability given that the synaptic vesicle release rate must fall to approximately 15-25% of what is considered the normal baseline level in order to substantially alter neurotransmission across the examined range of frequencies. We suggest that the high reliability provided by activation due to glutamate spillover could be used to conserve energy by reducing the required overall glutamate load at higher frequencies.