Abstract
Channelrhodopsins-2 (ChR2) are a class of light sensitive proteins that offer the ability to use light stimulation to regulate neural activity with millisecond precision. In order to address the limitations in the efficacy of the wild-type ChR2 (ChRwt) to achieve this objective, new variants of ChR2 that exhibit fast mon-exponential photocurrent decay characteristics have been recently developed and validated. In this paper, we investigate whether the framework of transition rate model with 4 states, primarily developed to mimic the biexponential photocurrent decay kinetics of ChRwt, as opposed to the low complexity 3 state model, is warranted to mimic the mono-exponential photocurrent decay kinetics of the newly developed fast ChR2 variants: ChETA (Gunaydin et al., Nature Neurosci. 13:387-392, 2010) and ChRET/TC (Berndt et al., Proc. Natl. Acad. Sci. 108:7595-7600, 2011). We begin by estimating the parameters of the 3-state and 4-state models from experimental data on the photocurrent kinetics of ChRwt, ChETA, and ChRET/TC. We then incorporate these models into a fast-spiking interneuron model (Wang and Buzsaki, J.Neurosci. 16:6402-6413, 1996) and a hippocampal pyramidal cell model (Golomb et al., J.Neurophysiol. 96:1912-1926, 2006) and investigate the extent to which the experimentally observed neural response to various optostimulation protocols can be captured by these models. We demonstrate that for all ChR2 variants investigated, the 4 state model implementation is better able to capture neural response consistent with experiments across wide range of optostimulation protocol. We conclude by analytically investigating the conditions under which the characteristic specific to the 3-state model, namely the monoexponential photocurrent decay of the newly developed variants of ChR2, can occur in the framework of the 4-state model.
Highlights
Optogenetics, an emerging optical neurostimulation technique, employs light activated ion channels to excite or suppress impulse activity in neurons with high temporal and spatial resolution (Deisseroth et al 2006)
For the 3-state model, using the parameters obtained in Table 2 and assuming that all ChR2 molecules are in the dark adapted closed state C prior to the optostimulation, we find that, independent of the ChR2 variant, the 3-state model is unable to reproduce an important feature of experimentally measured ChR2 photocurrent, namely the plateau to peak ChR2 photocurrent ratio R (Figure 2, panels A2 and Figure 10 panel A2 from Appendix)
We find that when the 3-state model for both ChRwt and ChRET/TC is implemented in the Gol model neuron, the model neuron elicits a significant number of additional spikes at the beginning of a 40 Hz optostimulation protocol, a feature that is inconsistent with experimental findings
Summary
Optogenetics, an emerging optical neurostimulation technique, employs light activated ion channels to excite or suppress impulse activity in neurons with high temporal and spatial resolution (Deisseroth et al 2006). A key merit of this technique is that it offers the ability to regulate neuronal activity with millisecond precision, which in turn allows for fine control of neuronal activity patterns in the brain region of interest. These proteins can be engineered to be expressed only in certain types of neurons (Cardin et al 2009). This technique offers capability to control neuronal activity with high degree of temporal accuracy in a cell specific manner, a significant advantage over traditional techniques such as electrical stimulation and pharmacological approaches
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