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A molecular light switch turns off neural activity

From single-cell recordings to whole-brain imaging, many current techniques allow scientists to monitor neural activity. However, testing the causal relationships between individual circuits and their proposed functions will require better tools to perturb cellular activity selectively. In a Technical Report on page 1383 of this issue, Richard Kramer and colleagues describe the use of a photoisomerizable ligand for rapid, reversible and spatially precise remote control of neural activity. Previous attempts to selectively manipulate activity in a particular set of neurons have been limited by inadequate temporal and spatial control. By engineering SPARK (synthetic photoisomerizable azobenzene-regulated K) channels that can be precisely and reversibly activated by light, Kramer and colleagues have overcome these limitations.

Voltage-gated potassium channels can be blocked by quaternary ammonium (QA) ions that bind to amino acids in the pore-lining region. Kramer and colleagues synthesized a tether attached to a QA group, which can covalently bind to a potassium channel that the authors modified to make the QA blocker the primary determinant of its gating. A section of the tether is photoisomerizable, meaning that its conformation can be changed by light. Shining light of a long wavelength (500 nm) shifts the tether into a long form, whereas light of a shorter wavelength (380 nm) shifts it to a shorter form. In the long form, the attached QA group can access and block the potassium channel pore, turning the channel off, but in the short form, the QA group does not reach the channel, allowing potassium ions to flow out of the cell. Because potassium efflux causes neurons to become hyperpolarized, the short-wavelength light can silence activity in hippocampal neurons exogenously expressing the SPARK channels. This new technique should find wide applicability in studies of circuit function and in other manipulations of neuronal activity. In addition, it should spark the development of more experimental, and perhaps therapeutic, tools.

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Allen, C. A molecular light switch turns off neural activity. Nat Neurosci 7, 1291 (2004). https://doi.org/10.1038/nn1204-1291

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