A Chemogenetic Approach for the Optical Monitoring of Voltage in Neurons

Article abstract of DOI:10.1002/anie.201812967

Optical monitoring of neuronal voltage using fluorescent indicators is a powerful approach for the interrogation of the cellular and molecular logic of the nervous system. Herein, a semisynthetic tethered voltage indicator (STeVI1) based upon nile red is described that displays voltage sensitivity when genetically targeted to neuronal membranes. This environmentally sensitive probe allows for wash-free imaging and faithfully detects supra- and sub-threshold activity in neurons.

Full text of DOI:10.1002/anie.201812967

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Accepted Article
Title: A chemogenetic approach for optical monitoring of voltage in
neurons
Authors: Mayya Sundukova, Efthymia Prifti, Annalisa Bucci, Kseniia
Kirillova, Joana Serrao, Luc Reymond, Miwa Umebayashi,
Ruud Hovius, Howard Riezman, Kai Johnsson, and Paul A
Heppenstall
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812967
Angew. Chem. 10.1002/ange.201812967
Link to VoR: http://dx.doi.org/10.1002/anie.201812967
http://dx.doi.org/10.1002/ange.201812967

10.1002/anie.201812967
Angewandte Chemie International Edition
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A chemogenetic approach for optical monitoring of voltage in
neurons
Mayya Sundukova*, Efthymia Prifti, Annalisa Bucci, Kseniia Kirillova, Joana Serrao, Luc Reymond,
Miwa Umebayashi, Ruud Hovius, Howard Riezman, Kai Johnsson, Paul A. Heppenstall*
Abstract: Optical monitoring of neuronal voltage using fluorescent
indicators have been proposed which combine the superior
optical properties of small-molecule fluorophores with genetically
encoded voltage sensors[11]. Examples include a precursor VSD
that is converted to an active membrane-bound dye by a
genetically encoded enzyme[12] , and click chemistry- and
enzyme-mediated ligation of organic fluorophores to rhodopsin to
indicators is a powerful approach for interrogation of the cellular and
molecular logic of the nervous system. Here we describe
a
Semisynthetic Tethered Voltage Indicator (STeVI1) based upon Nile
Red that displays voltage sensitivity when genetically targeted to
neuronal membranes. This environmentally sensitive probe allows for
wash-free imaging and faithfully detects supra- and subthreshold
activity in neurons.
function as FRET donors[13,14]
.
Here we considered an alternative approach for hybrid voltage
sensor design; localization of a synthetic voltage indicator to cells
of interest using genetically encoded protein tags[15]. We focused
on enzyme-based small protein tags such as the self-modifying
enzyme SNAP -tag[16], and transferase-mediated labeling of the
acyl carrier protein (ACP)-tag[17,18], as these technologies allow for
rapid, irreversible labeling, and are compatible with in vivo
imaging[19]. For the VSD component we found that derivatives of
Nile Red, an environment-sensitive (‘fluorogenic’) dye that shows
fluorescence enhancement upon transition from aqueous to
hydrophobic solvent[20,21], register membrane potential with high
fidelity. We named the resulting voltage sensor Semisynthetic
Tethered Voltage Indicator 1 (STeVI1).
We initially investigated the voltage sensitivity of the Nile Red-
derivative NR12S (Fig.1a), a fluorogenic probe which contains a
zwitterionic group and hydrocarbon chain, and has been used to
monitor lipid order[22,23]. NR12S readily labeled the membranes of
HEK293T cells with a signal-to-noise ratio (SNR) of 10.45±1.3
under wash-free conditions (SI Fig. 1 and SI Fig.4a). To quantify
its voltage sensitivity, we used whole cell voltage clamp to control
membrane potential, and simultaneously recorded the epi-
fluorescence signal from the membranes at an illumination
irradiance of 12 mW/mm2. Upon application of rectangular
depolarizing voltage steps of various magnitudes from a –60 mV
holding potential, fluorescence signal decreased linearly in the
physiological range of membrane potential (R2=0.97, Fig.1b).
Voltage sensitivity expressed as fractional fluorescence change
F/F% (normalized to fluorescence at a holding potential of – 60
mV) achieved – 5.1 ± 0.4 % per 100 mV (n= 10 cells). NR12S
fluorescence responded to applied voltage steps with a mean rise
time on=1.9 ± 0.4 ms and a weighted decay time off=1.9 ± 0.2
ms (the fast component represented >85% of response).
Complementation and substitution of electrophysiology methods
with non-invasive optical imaging of neuronal activity is a major
technological challenge in neuroscience[1]. Calcium imaging with
genetically encoded indicators is widely used to interrogate the
connectivity and function of neural circuits at different spatial and
temporal resolutions[2]. However, as a surrogate for underlying
electrical activity, calcium imaging has a number of shortcomings.
For example, calcium indicators lack the sensitivity to register
subthreshold activity, and their slow kinetics and the nature of the
calcium transient itself often preclude recording of high-frequency
firing. Direct readout of neuronal membrane voltage is therefore
necessary for imaging subthreshold and inhibitory activity, and for
investigating fast-coordinated phenomena[3]. As such, significant
efforts are being invested in developing probes and improving
microscopy for optical monitoring of voltage[4–7]
.
Fluorescent indicators for membrane potential can be divided into
two groups; synthetic voltage sensitive dyes (VSD)[4], and
genetically encoded voltage indicators (GEVI) based upon
voltage sensitive proteins such as opsins, channels and
phosphatases[8]. Organic VSDs possess excellent photophysical
properties and fast kinetics for live imaging. However, their
application in vivo is limited by unspecific staining of tissue,
compromising signal-to-noise ratio (SNR) and cell identity[4].
GEVIs provide a valuable alternative as they can be genetically
targeted to subsets of cells[7,9,10]. However, GEVIs often suffer
from low brightness, poor photostability and slow kinetics[5,7]. They
may also localize poorly to the plasma membrane and exhibit
cellular toxicity. To circumvent these problems, hybrid voltage
We further enquired whether NR12S could report action
potentials in dissociated dorsal root ganglion (DRG) sensory
neurons. Imaging at 333 fps allowed for detection of current
injection-triggered action potentials in single trials, with a F /F%
per action potential of – 1.9 ± 0.3% (n=4 neurons) corresponding
to a peak SNR of 9.5 ± 1.6 (Fig. 1c-d). Because of the large
dynamic range of the probe and its fast kinetics, NR12S
fluorescence signals closely followed the action potential shape,
permitting the optical monitoring of sub- and suprathreshold
neuronal events. Moreover, the orange emission of membrane-
bound NR12S (max = 581 ± 1 nm in live cells, SI Fig. 2), favors
this fluorophore over green-emitting VSDs and GEVIs for use in
vivo. Membrane depolarization did not cause a detectable shift in
Dr. Mayya Sundukova*, Annalisa Bucci, Kseniia Kirillova, Joana
Serrao, Dr. Paul A. Heppenstall*
Molecular Medicine Partnership Unit (MMPU), 69117 Heidelberg,
Germany
Epigenetics and Neurobiology Unit, EMBL Rome, via Ramarini 32,
Monterotondo, Italy
* E-mail: mayya.sundukova@gmail.com, paul.heppenstall@embl.de
Prof. Kai Johnsson
Department of Chemical Biology, Max Planck Institute for Medical
Research, 69120 Heidelberg, Germany
Dr. Luc Reymond, Dr. Ruud Hovius Prof. Kai Johnsson
Ecole Polytechnique Federale de Lausanne, ISIC, NCCR in Chemical
Biology, 1015 Lausanne, Switzerland
Dr. Miwa Umebayashi, Prof. Howard Riezman
University of Geneva, Department of Biochemistry, 1211 Geneva,
Switzerland
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201812967
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the emission spectrum of NR12S as observed in lipid order
monitoring[22] (SI Fig.2b), therefore we recorded the red region of
NR12S emission to detect its fluorescence changes (Fig.1).
selected the ACP-tag (8-kDa) and synthesized Nile Red–
Coenzyme A (CoA) conjugates with variable PEG repeats (n=5,
~2.5 nm; n=11; Fig. 2b, SI Scheme 2). The ACP-tag was
expressed on the surface of HEK293T cells via a GPI anchor, and
functionality was verified by labeling with CoA-ATTO532 in the
presence of phosphopantetheinyl transferase (SFP-synthase, SI
Fig. 4d). Nile Red compounds also specifically labeled ACP-GPI
expressing HEK293T cells with minimal background (Fig. 2c, SI
Fig. 4 and 5), SNR of the membrane fluorescence over
background under wash-free conditions were 10.7±1.5 for CoA-
PEG11-NR and 12.4 ±1.3 for CoA-PEG5-NR.
Figure 1. Nile Red based probe NR12S detects membrane voltage change. a)
Schematic of Nile Red-based NR12S probe in the membrane. Depolarization of
the cell membrane leads to decreased fluorescence intensity. b) Mean response
of NR12S to changes in transmembrane potential in patch-clamped HEK293T
cells. Error bars represent 95% C.I. (n=6 cells). Inset graph. Fluorescence
responses in a typical NR12S-labeled HEK293T cell subjected to 500 ms-long
square voltage steps of various magnitudes. Responses were normalized to
fluorescence at the −60-mV holding potential. Line colors match the colors of
data points at the main graph. c) Typical NR12S fluorescence response to single
trial recordings of action potentials DRG neurons triggered by current injections
of incrementing amplitude (80 ms, 80 - 560 pA, top trace). d) NR12S response
to single trial recordings of action potentials in DRG neurons triggered by current
injection (80 ms, 600 pA). Full width at half-maximum of the action potential of
the voltage trace (left) was 4.5 ms and of its fluorescence readout was 6.3 ms
(right). Images were recorded using an epi-fluorescent microscope, every 5 ms
for b) and 3 ms for c) - d). Here and subsequently, excitation light was filtered
with a bandpass filter (360-540 nm); emission light was filtered with a 570-640
nm filter. Cells were labeled at 500 nM of NR12S for 7 mins at room temperature.
Figure 2. Genetic targeting of Nile Red based voltage indicators. a) Schematic
illustration of STeVI1 - Nile Red derivatives tethered with a molecular linker to a
protein tag. b) Structures of ACP-targeted Nile Red derivatives with various
linker lengths. c) Mean responses of CoA-PEGn-NR compounds to changes in
transmembrane potential in patch-clamped HEK293T cells, PEG repeats n=5,
11. Error bars represent 95% C.I. (n=8-9 cells). Inset image. Representative
confocal images of HEK293T cells transfected with ACP-GPI and labeled with
1 M CoA-PEG11-NR. Maximum projection of 19 z-stacks of z=0.4m. LUT is
inverted for illustration purposes. Scale bar 10 m. Inset graph. Typical
fluorescence responses of CoA-PEG11-NR in a HEK293T cell subjected to a
500 ms-long square voltage steps of various magnitudes. Responses were
normalized to fluorescence at the −60-mV holding potential. Line colors
correspond to different membrane voltages. d) Fluorescence response (bottom)
of CoA-PEG11-NR bound to ACP-GPI to rectangular voltage steps of 160 mV,
applied at ~10 Hz (10 ms-duration, top). Images were recorded using an epi-
fluorescent microscope, every 5 ms for c) and 2 ms for d).
We next asked whether Nile Red derivatives could be genetically
localized to cells of interest through binding to a protein tag
(Fig.2a). We first synthesized Nile Red derivatives that bind to
SNAP-tag, and expressed the corresponding tag on the
extracellular
surface
of
HEK293T
cells
via
a
glycosylphosphatidylinositol (GPI) anchor signal sequence (SI Fig.
3a). Polyethylene glycol (PEG) linkers of n=11 repeats (~4.8 nm)
and charged groups were introduced in the molecules to improve
water solubility and reduce nonspecific interactions[24,25] (SI
Scheme 1). Although compounds specifically labeled membranes
of cells expressing SNAP-tag, negligible voltage sensitivity was
observed as tested by simultaneous patch clamp and imaging (SI
Fig. 3c-d). Measurements of emission spectra of the compounds
from live cells revealed red-shifted fluorescence in comparison to
NR12S (SI Table 1), suggesting that compounds were probing
hydrophobic surfaces[26] of the protein tag rather than the
membrane environment.
ACP-targeted compounds displayed
a significant voltage
sensitivity in HEK293T cells which, similar to NR12S, was almost
linear (R2=0.97 for PEG11, R2=0.96 for PEG5; Fig. 2c and SI Movie
1). Fractional fluorescence change per 100 mV was – 5.5 ± 0.4 %
To resolve this issue, we reasoned that a smaller tag may give
the probe better access to the membrane electric field. We
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and – 4.9 ± 0.3 % for the CoA-PEG5-NR and CoA-PEG11-NR
compounds (n=8 cells). This is comparable to the voltage
sensitivity of the non-targetable hemicyanine dye di-4-ANEPPS[27]
We tested the ability of ACP-tag targeted probes to detect trains
of action potential-like voltage steps in HEK293T cells (Fig.2d).
The kinetics of the CoA-PEG11-NR fluorescence response to
neurons[28] (see for example SI Fig. 7). We further investigated
whether the Nile Red probes would allow for the detection of
spontaneous activity in neuronal processes. Wide-field
fluorescence imaging of neurons labeled with CoA-PEG11-NR
faithfully reported spontaneous spikes at the level of cell body and
axons in single-trial optical recordings (Fig. 4, SI Movie 3). F/F %
amplitude per spontaneous spike at ~10 Hz was -2.3 ± 0.1 % at
the cell body membrane corresponding to a peak SNR of 7.6 ±
0.1.
.
applied voltage steps was fast, with a mean rise time
on =1.8 ±
0.2 ms and a weighted decay time off = 2.6 ± 0.1 ms (the fast
component represented >85% of the response).
We next investigated voltage sensitivity of CoA-PEGn-NR probes
in isolated DRG neurons. ACP-GPI was expressed via
recombinant adeno-associated virus (AAV)-mediated gene
delivery, and functionality was verified by labeling with CoA-TMR
(SI Fig. 6). STeVI1 compounds selectively labeled the neuronal
membranes of cell body and axons with negligible intracellular
signal (Fig.3a, in part due to charged groups in the CoA, Fig.2b)
and no toxicity. Neurons were patch clamped, and action
potentials were evoked via current injection. CoA-PEGn-NR
compounds tracked single and trains of action potentials in the
cell body (Fig.3b,c, SI Fig. 7, SI Movie 2). F/F % amplitudes per
action potential reached – 2.0 ± 0.3 % for PEG11 and – 2.2 ± 0.3 %
for PEG5 respectively (n=5 neurons). Corresponding action
potential peak SNR were 13.8 ± 1.5 for PEG11 and 16.2 ± 3.0 for
PEG5. ACP-GPI expression and probe insertion in the membrane
did not cause significant differences in action potential amplitude
and duration, or membrane capacitance between control and
labeled neurons (One-Way ANOVA, p=0.11, p=0.72 and p=0.58).
Figure 4. Tethered Nile Red indicators tracks spontaneously occurring action
potentials. a) Wide-field image of DRG culture, expressing ACP-GPI and
labelled with CoA-PEG11-NR. Cell body and individual axons are outlined with
colored ROIs. Scale bar is 10 m. LUT image is inverted. b) Membrane potential
(top trace, black) was recorded from the cell body under current clamp mode
(no current injection). Epi-fluorescence (measured at 100 fps) from single-trial
optical recordings for the color-matched somatic and axon areas (colored
traces) highlighted in the image. No fluorescence signals were observed for
axon area 5 (another neuron).
In conclusion, we demonstrate that Nile Red derivatives display a
voltage sensitivity that can be exploited to monitor membrane
potential in genetically tagged cells. Future studies will explore the
contribution of possible mechanisms underlying Nile Red voltage
sensitivity such as solvatochromism, electrochromism and
intermolecular interactions. STeVI1 probes were able to detect
the shape of subthreshold depolarizations and fast neuronal
activity with sensitivity comparable to GEVIs, but required 2-fold
less light power (comparison data and references in SI Table 2).
Key to the success of the approach was the small size of the ACP-
tag which allowed for positioning of the Nile Red in the membrane
environment. In future applications, this small size may also
enable insertion of the ACP-tag in exposed loops of channels or
other membrane proteins, to direct expression to defined
neuronal subcellular compartments, such as axon terminals,
soma or dendrites.
Figure 3. Tethered Nile Red indicators detect evoked and spontaneous
neuronal activity. a) Representative confocal images of cultured DRG neurons
expressing ACP-GPI via rAAV-mediated delivery. Top, brightfield image, bottom,
maximum projection of 34 z-stacks of z=0.4m. Scale bar 10 m. b) Typical
CoA-PEG11-NR fluorescence response in a single trial recording of an action
potential in labeled DRG neurons triggered by current injection (80 ms, 80 pA).
Full width at half-maximum of the action potential of the voltage trace (top) was
2 ms and of its fluorescence readout was 5 ms (bottom). c) Representative
single-trial recordings of current-triggered injection (80 ms, 80 pA) action
potentials in DRG neurons with 2 M CoA-PEG11-NR probe bound to ACP-GPI.
Images were recorded using epi-fluorescence microscope at 500 fps. d)
Fluorescence change vs. membrane potential (mean ± standard deviation)
displays the linearity of the voltage sensitivity in neurons (data from the trace in
c). Fluorescence changes corresponding to membrane voltage binned to 10 mV
intervals were averaged and then fitted with a linear function.
Acknowledgements
Importantly, in neurons Nile Red fluorescence reported voltage
changes linearly (R2=0.94, slope = -0.027; Fig. 2d). Fluorescent
traces from cell membranes closely mimicked the shape of
electrophysiological recorded action potentials, as evidenced by
the close match of full width at half-maximum between the
fluorescent and electrical traces (Fig. 1c and 3b). Indeed, from the
voltage imaging, it was possible to discern the inflection on the
falling phase of action potentials that is indicative of nociceptive
We would like to thank EMBL Rome Microscopy Facility, Genetic
& Viral Engineering Facility, mouse husbandry Facility and A.
Gargano for help with neuronal cultures. We would like to
acknowledge Interdisciplinary Postdoctoral Fellowship (EIPOD,
EMBL, and EU Marie Curie Actions COFUND II grant) and IBSA
Foundation for Scientific Research for support of M.S., European
Union Seventh Framework Program (FP7 2007-2013) under
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and support from the National Centre for Competence in
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Keywords: voltage imaging • protein tags • fluorogenic probes •
membrane potential probes • genetic targeting
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10.1002/anie.201812967
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COMMUNICATION
Here we describe a Semisynthetic
Tethered Voltage Indicator (STeVI1)
based upon Nile Red that displays
voltage sensitivity when genetically
targeted to neuronal membranes. This
environmentally sensitive probe allows
for wash-free imaging and faithfully
detects supra- and subthreshold
activity in neurons.
Mayya Sundukova*, Efthymia Prifti,
Annalisa Bucci, Kseniia Kirillova, Joana
Serrao, Luc Reymond, Miwa
Umebayashi, Ruud Hovius, Howard
Riezman, Kai Johnsson, Paul A.
Heppenstall*
Page No. – Page No.
A chemogenetic approach for optical
monitoring of voltage in neurons
This article is protected by copyright. All rights reserved.