High-performance genetically targetable optical neural silencing by light-driven proton pumps.

Area of Science:

• Neuroscience
• Optogenetics
• Molecular Biology

Background:

• Precise temporal control over genetically specified neuron activity is crucial for understanding neural circuits, behavior, and disease.
• Existing optogenetic methods for neuronal silencing have limitations in power, safety, or versatility.

Purpose of the Study:

• To investigate the potential of light-driven outward proton pumps for effective and safe neural silencing.
• To explore the utility of archaerhodopsin-3 (Arch) and Mac proton pumps for optogenetic applications.

Main Methods:

• Viral expression of archaerhodopsin-3 (Arch) from Halorubrum sodomense in mouse cortex.
• Illumination with yellow light to activate Arch and induce neural silencing.
• Expression and activation of Mac proton pump from Leptosphaeria maculans with blue-green light.

Main Results:

• Arch enabled near-100% silencing of neurons in awake mice with yellow light, achieving high currents at low light powers.
• Arch demonstrated rapid recovery from light-induced inactivation, unlike chloride pumps.
• Mac enabled neural silencing with blue light, allowing for dual-color optogenetic control when combined with red-light activatable tools.

Conclusions:

• Light-driven proton pumps, such as Arch and Mac, are high-performance and versatile optogenetic tools for neural silencing.
• These tools are well-tolerated in neurons and suitable for modulating significant brain volumes over behaviorally relevant timescales.
• Proton pump diversity offers innovative solutions for broad neuroscientific, biological, neurological, and psychiatric investigations.