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Vibrodissociation of Neurons from Rodent Brain Slices to Study Synaptic Transmission and Image Presynaptic Terminals
Published on: May 25, 2011
Subthreshold electric fields bidirectionally modulate neurotransmitter release through axon polarization
Aman S Aberra1, Madelyn W Miles1, Michael B Hoppa1
1Dept. of Biological Sciences, Dartmouth College, Hanover, NH, USA.
Background:
Subthreshold electric fields modulate brain activity and show promise in several therapeutic applications. Although therapeutic electric fields are often uniform at the cellular level, they generate non-uniform membrane polarization within neurons due to their complex morphologies. Despite extensive modeling of neuronal membrane polarization by electric fields, subthreshold axonal polarization has not been measured and the resulting effects on neurotransmitter release are unknown.
Objective:
To investigate the mechanisms by which subthreshold electric fields alter synaptic function using next-generation optogenetic indicators.
Methods:
We combined noninvasive optogenetic indicators of voltage, glutamate, and calcium release to study the subcellular response to subthreshold electric fields in single neurons at high spatiotemporal resolution.
Results:
We first captured the spatiotemporal profile of membrane polarization produced by uniform electric fields within individual neurons. Clinically relevant electric field intensities produced small polarizations of presynaptic boutons (<5 mV), yet caused rapid and powerful modulation of neurotransmitter release. We determined that subthreshold electric fields drive these effects by shifting resting calcium levels and altering the number of synaptic vesicles participating in neurotransmission.
Conclusions:
Using subcellular optical measurements, we directly resolved the effects of electric fields on axonal and synaptic function, overcoming fundamental limitations of classical electrophysiology. Our results provide key insights into the cellular mechanisms of subthreshold electric field stimulation paradigms and may inform the design of neuromodulation therapies.
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