Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse
Abstract
Synapses of glutamatergic mossy fibers onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC's large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institute of Neurological Disorders and Stroke (NS028901)
- Laurence O Trussell
National Institute of Neurological Disorders and Stroke (NS116798)
- Laurence O Trussell
National Institute on Deafness and Other Communication Disorders (DC004450)
- Laurence O Trussell
National Institute on Deafness and Other Communication Disorders (DC016905)
- Timothy S Balmer
National Institute on Deafness and Other Communication Disorders (DC014878)
- Timothy S Balmer
National Institute on Deafness and Other Communication Disorders (DC012454)
- Carolina Borges-Merjane
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were performed under the approval of the institutional animal care and use committee (IACUC) of Oregon Health and Science University, assurance #A3304-01.
Copyright
© 2021, Balmer et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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