Nanoactuator for Neuronal Optoporation.

Area of Science:

• Neuroscience
• Biophysics
• Materials Science

Background:

• High spatial-temporal resolution control of neuronal activity is crucial in neuroscience.
• Optogenetics offers precise control but requires genetic modification; there's a need for non-genetic tools.
• Nongenetic membrane-targeted nanomachines are sought to modulate neuronal electrical states.

Purpose of the Study:

• To engineer and characterize a photoswitchable conjugated compound (BV-1) for light-driven neuronal modulation.
• To investigate the mechanism of BV-1's effect on neuronal membranes.
• To explore BV-1's potential applications in neuroscience, including photostimulation and cell ablation.

Main Methods:

• Engineering and characterization of the photoswitchable compound BV-1.
• Electrophysiological recordings on primary neurons and nonexcitable cells.
• Time-resolved atomic force microscopy and molecular dynamics simulations on lipid bilayers.
• In vivo and ex vivo experiments on retinal explants and primary visual cortex.

Main Results:

• BV-1 spontaneously partitions into neuronal membranes and forms light-induced pores upon cyan light stimulation.
• Light-induced pore formation decreases membrane resistance, increases cation permeability, and causes neuronal depolarization and firing.
• Mechanism involves light-driven oxidation of phospholipids, reduced membrane tension, and increased fluidity.
• BV-1 enables rapid switching to perforated whole-cell patch-clamp configuration and can induce neuronal death with sustained light.

Conclusions:

• BV-1 acts as a versatile molecular nanomachine for light-controlled membrane poration.
• It allows for tunable modulation of neuronal activity, from stimulation to cell death, based on light patterns.
• BV-1 offers a promising non-genetic tool for advanced neuroscience research and potential therapeutic applications.