Optogenetics

Traditional methods for the functional analysis of neurons have relied on direct stimulation by tiny electrodes, although the effectiveness is undermined by the limited spatial and temporal precision with which individual cells can be selectively targeted. As such, the recent emergence of optogenetic tools — genetically encoded switches that allow neurons to be turned on or off with bursts of light — promises to revolutionize the study of how neurons operate singly and as members of larger networks, and could ultimately offer new hope for patients suffering from vision impairment or neurological disorders such as epilepsy or Parkinson’s disease.

TURN-ONS AND TURN-OFFS

At a basic level, the nervous system can be thought of as a highly complex electrical circuit. Every neuron contains a variety of pump and channel proteins that control the flow of ions across its membrane, maintaining a negative membrane potential in the resting neuron. Activation signals, for example from neurotransmitters, cause positively-charged ions to flow into the cell from the external environment via these channel proteins, resulting in membrane depolarization. At a certain threshold, this triggers an action potential — a rapid influx of sodium ions that effectively reverses the voltage inside the cell, initiating a chain reaction of sodium-ion influx that propagates down the length of the axon, eventually causing the release of neurotransmitters that stimulate or inhibit the production of electrical impulses in neighbouring neurons.

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Fig. 1 | Schematic representation of the action of channelrhodopsin and halorhodopsin on neural cells. Activation... [more]

Fig. 1 | Schematic representation of the action of channelrhodopsin and halorhodopsin on neural cells. Activation with blue light opens the channel (channelrhodopsin), allowing in sodium ions and turning the neuron ‘on’; yellow light (onto halorhodopsin) introduces chloride ions, turning the neuron ‘off’. [less]

<b>Fig. 1 | Schematic representation of the action of channelrhodopsin and halorhodopsin on neural cells.</b> Activation with blue light opens the channel (channelrhodopsin), allowing in sodium ions and turning the neuron ‘on’; yellow light (onto halorhodopsin) introduces chloride ions, turning the neuron ‘off’.

© Courtesy of Gary Carlson / Science Photo Library.

© Courtesy of Gary Carlson / Science Photo Library.

Microelectrodes have historically proven useful for the direct stimulation (less so for the inhibition) of neurons in neurophysiological studies, although the poor resolution limit imposed by this experimental regime has left neuroscientists hungry for alternatives. The development of ‘caged’ neurotransmitters — chemically modified to remain inactive unless triggered (‘uncaged’) by laser illumination — and chemically modified photo-switchable ion channels have allowed notable improvements in precision for functional studies, although with limited possibilities for application.

However, the real revolution came with the discovery of the algae protein channelrhodopsin, which allows influx of positive ions in response to illumination with blue light to act as an ‘on’ switch¹ (Fig. 1). A few years later, scientists recognized the potential of the archaeal protein halo- rhodopsin, which triggers influx of negatively-charged chlorine ions in response to yellow light and thereby hyperpolarizes the cell, to act as an ‘off’ switch². Both of these proteins can readily be introduced into target cells by various techniques, allowing scientists to rapidly and accurately turn individual neurons on and off without the need for additional drugs or chemicals.