Spotlight on movement disorders: What optogenetics has to offer

Abstract

Elucidating the neuronal mechanisms underlying movement disorders is a major challenge because of the intricacy of the relevant neural circuits, which are characterized by diverse cell types and complex connectivity. A major limitation of traditional techniques, such as electrical stimulation or lesions, is that individual elements of a neural circuit cannot be selectively manipulated. Moreover, available treatments are largely based on trial and error rather than a detailed understanding of the circuit mechanisms. Gaps in our knowledge of the circuit mechanisms for movement disorders, as well as mechanisms underlying known treatments such as deep brain stimulation, make it difficult to design new and improved treatment options. In this perspective, we discuss how optogenetics, which allows researchers to use light to manipulate neuronal activity, can contribute to the understanding and treatment of movement disorders. We outline the advantages and limitations of optogenetics and discuss examples of studies that have used this tool to clarify the role of the basal ganglia circuitry in movement.

Keywords: Channelrhodopsin; DBS; Parkinson's disease; dystonia.

Figure 1. Schematic illustration of common opsins

(a) When blue light hits channelrhodopsin-2, the channel opens allowing influx of cations. (b) When yellow light hits halorhodopsin, chloride is pumped into the cell. Adapted from .

Figure 2. Strategy for Cre-dependent expression of opsins

The example shown uses the double floxed inverted open reading frame strategy. Opsin-encoding virus can be injected into a transgenic mouse expressing Cre recombinase in a molecularly defined subset of cells. In the presence of Cre recombinase, the opsin-encoding region is inverted, allowing translation into functional protein within these cells. pr, ubiquitous promoter. Adapted from .

Figure 3. Approaches for dissection of neural circuits using optogenetics

Schematic illustration of stimulation of molecularly defined neurons using ChR2 as an example. (a) Selective expression of ChR2 in a molecularly defined neuron population allows optical activation of a subset of cell bodies embedded within heterogeneous tissue. (b) When ChR2 is expressed in a molecularly defined subset of projection neurons, distal axon terminals may be targeted with optical stimulation. (c) Stimulation of a molecularly defined interneuron population can be used to inhibit post-synaptic projection neurons.