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Review
, 16 (7), 816-23

Optogenetic Pharmacology for Control of Native Neuronal Signaling Proteins

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Review

Optogenetic Pharmacology for Control of Native Neuronal Signaling Proteins

Richard H Kramer et al. Nat Neurosci.

Abstract

The optical neuroscience revolution is transforming how we study neural circuits. By providing a precise way to manipulate endogenous neuronal signaling proteins, it also has the potential to transform our understanding of molecular neuroscience. Recent advances in chemical biology have produced light-sensitive compounds that photoregulate a wide variety of proteins underlying signaling between and within neurons. Chemical tools for optopharmacology include caged agonists and antagonists and reversibly photoswitchable ligands. These reagents act on voltage-gated ion channels and neurotransmitter receptors, enabling control of neuronal signaling with a high degree of spatial and temporal precision. By covalently attaching photoswitch molecules to genetically tagged proteins, the newly emerging methodology of optogenetic pharmacology allows biochemically precise control in targeted subsets of neurons. Now that the tools for manipulating endogenous neuronal signaling proteins are available, they can be implemented in vivo to enhance our understanding of the molecular bases of brain function and dysfunctions.

Figures

Figure 1
Figure 1
Photochemical tools for controlling neural function. (a) Optogenetics. (b) Optopharmacology. (c) Optogenetic pharmacology.
Figure 2
Figure 2
Three methods of photocontrol for mapping mechanisms of brain function. (a) Left, optogenetics with microbial opsins allows photocontrol of the activity of neurons expressing the foreign gene, such as with ChR2, without any exogenous cofactors. Right, the opsin can be targeted to a specific cell type using genetic approaches permitting one to selectively control the activity of a presynaptic population’s activity (green cells) while monitoring the functional effect on postsynaptic cells downstream. (b) Optopharmacology, such as with glutamate uncaging, allows photocontrol of any neuron that expresses the appropriate receptor (in this case, glutamate receptors). Two-photon uncaging can locally activate receptors in a small region, for example, on a dendritic spine (left). Laser-scanning photostimulation can activate receptors on a large scale, for example, in a population of presynaptic neurons (right). (c) Optogenetic pharmacology allows photocontrol of native receptor subtypes. This is receptor specific (left) and can be cell-type specific (right, green cells).
Figure 3
Figure 3
Optogenetic pharmacology enables photocontrol of ion channels and neurotransmitter receptors in mouse hippocampal neurons. (a) In a neuron expressing photosensitive SK2 channels, depolarization leads to an afterhypolarizing tail current (IAHP) that can be modulated by light. Depolarization causes Ca2+ influx and SK2 is a Ca2+-activated K+ channel. (b) Photocontrol of SK2 modulates the amplitude of NMDA receptor–mediated excitatory postsynaptic potentials (EPSPs). NMDA receptor activation causes Ca2+ influx, which activates nearby SK2 channels. Recordings are from a CA1 neuron in a hippocampal slice that virally expressed photoswitch-ready SK2. Modified from ref. . (c) In a neuron expressing photosensitive mGluR2 receptors, autaptic excitatory postsynaptic current (EPSC) amplitude can be regulated by light. (d) Photosensitive mGluR2 enables light modulation of presynaptic release. Photocontrol of mGluR2 modulates presynaptic voltage-gated Ca2+, leading to changes in paired-pulse facilitation, an indicator of release probability. Autaptic recordings are from a hippocampal neuron in primary culture. Modified from ref. . In all panels, green traces were obtained in 500-nm light (photoswitch in trans) and violet traces in 380-nm light (photoswitch in cis).
Figure 4
Figure 4
Expression options for optogenetic pharmacology. (a) The photoswitch-ready protein (gray) can be overexpressed to form exogenous light-sensitive channels that co-exist with native light-insensitive channels (white). Overall channel number is increased. (b) The photoswitch-ready protein may form heteromers with endogenous subunits, thereby conferring light sensitivity onto the hybrid channels. Depending on the availability of the endogenous subunits, hybrid light-sensitive channels may partially or fully replace the native light-insensitive channels. Overall channel number may or may not be increased. (c) The photoswitch-ready protein can genetically replace the wild-type protein in a knock-in mouse. All of the channels are light-sensitive and overall channel number is unchanged.

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