Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7

Caldwell, John H.; Herin, Greta Ann; Nagel, Georg; Bamberg, Ernst; Scheschonka, Astrid; Betz, Heinrich

doi:10.1074/jbc.m802593200

Cited by 22 publications

(18 citation statements)

References 42 publications

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“…The optogenetic stimuli each lasted 10 ms and ChR2 has an estimated decay constant of 15 ms (39). The phasic GABA pulse, on the other hand, lasted only about 5-6 ms with a much shorter decay constant of 5.6 ms. Because ChR2 causes a more sustained increase in voltage and is directly permeable to calcium (40,41), it causes a much greater increase in intracellular calcium and is therefore effective in shifting the molecular clock, whereas the phasic GABA signal is not. Thus, although we find certain kinds of oscillatory electrical activity can cause calcium influx and shift the molecular clock in a similar way to the tonic GABA signal, the irregular firing of average SCN neurons that causes phasic GABA release does not.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping

DeWoskin

Myung

Belle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

158

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The suprachiasmatic nuclei (SCN), the central circadian pacemakers in mammals, comprise a multiscale neuronal system that times daily events. We use recent advances in graphics processing unit computing to generate a multiscale model for the SCN that resolves cellular electrical activity down to the timescale of individual action potentials and the intracellular molecular events that generate circadian rhythms. We use the model to study the role of the neurotransmitter GABA in synchronizing circadian rhythms among individual SCN neurons, a topic of much debate in the circadian community. The model predicts that GABA signaling has two components: phasic (fast) and tonic (slow). Phasic GABA postsynaptic currents are released after action potentials, and can both increase or decrease firing rate, depending on their timing in the interspike interval, a modeling hypothesis we experimentally validate; this allows flexibility in the timing of circadian output signals. Phasic GABA, however, does not significantly affect molecular timekeeping. The tonic GABA signal is released when cells become very excited and depolarized; it changes the excitability of neurons in the network, can shift molecular rhythms, and affects SCN synchrony. We measure which neurons are excited or inhibited by GABA across the day and find GABA-excited neurons are synchronized by-and GABA-inhibited neurons repelled from-this tonic GABA signal, which modulates the synchrony in the SCN provided by other signaling molecules. Our mathematical model also provides an important tool for circadian research, and a model computational system for the many multiscale projects currently studying brain function.

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Section: Discussionmentioning

confidence: 99%

Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping

DeWoskin

Myung

Belle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

126

158

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“…While native sodium channels are central to this mechanism, other native membrane components may have contributed. For example, other transmembrane channels4344 and cellular receptors45 display functional changes upon ChR2 evoked membrane depolarization.…”

Section: Discussionmentioning

confidence: 99%

Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2

Liske

Xiang

Anikeeva

et al. 2013

Sci Rep

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The effect of electrical stimulation on neuronal membrane potential is frequency dependent. Low frequency electrical stimulation can evoke action potentials, whereas high frequency stimulation can inhibit action potential transmission. Optical stimulation of channelrhodopsin-2 (ChR2) expressed in neuronal membranes can also excite action potentials. However, it is unknown whether optical stimulation of ChR2-expressing neurons produces a transition from excitation to inhibition with increasing light pulse frequencies. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. We also demonstrate all-optical single-wavelength control of neuronal excitation and inhibition without co-expression of inhibitory and excitatory opsins. This all-optical system is free from stimulation-induced electrical artifacts and thus provides a new approach to investigate mechanisms of high frequency inhibition in neuronal circuits in vivo and in vitro.T he ability to both excite and inhibit neuronal activity with electrical stimulation of different frequencies has important implications for basic and clinical neuroscience. Low frequency electrical stimulation depolarizes neuronal membranes and evokes action potentials, whereas higher frequencies, ranging from 200 Hz to 30 kHz 1 as well as continuous depolarizing stimulation, have been used to inhibit action potentials in both central 2,3 and peripheral neurons 1,4-17 . High frequency electrical stimulation has been clinically implemented [18][19][20] for cases in which inhibition of neuronal activity is desired, such as the treatment of pain 19,20 . While this is a valuable approach, the mechanisms underlying the frequency-dependent transition from excitation to inhibition remain unclear, in part due to stimulation-induced electrical artifacts that interfere with electrophysiological recordings 2,12,21 . Furthermore, low and high frequency electrical stimulation have limited ability to control activity in defined subsets of collocated neurons. Optogenetics is a powerful technique enabling activation and inhibition of specific cell types that are collocated 22,23 .Previous studies have sought to simultaneously excite and inhibit a population of neurons using optogenetics [24][25][26][27] . These efforts used specialized viral and genetic approaches to achieve co-expression of ChR2 with an inhibitory opsin, such as halorhodopsin (NpHR), in the same neurons. Thus far, co-expression has been achieved in vitro [24][25][26] and in vivo in zebrafish 27 . Excitation and inhibition were achieved in these studies by optical stimulation of two opsins with two light wavelengths of sufficient spectral separation. While optical stimulation of ChR2 is typically used to evoke neuronal activity, several studies observed inhibition of neuronal activity during high frequency blue light stimulation of ChR2-expressing neurons in the mouse brain [28][29][30] . In most cases the inhibition was produced by excitation of interneurons (e...

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“…2). In the presence of extracellular Ca ++ and at negative holding potentials, CatCh currents showed a dramatic increase in amplitude during illumination due to a superimposed outward current which resembles that of calcium activated chloride channels (CaCC) 15,16 (Fig. 2c).…”

Section: Molecular Properties and Selectivity Of Catchmentioning

confidence: 99%

Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh

et al. 2011

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Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7

Cited by 22 publications

References 42 publications

Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping

Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping

Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2

Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh

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