Investigating the diferences in ion channel properties between ON and OFF ganglion cells: a combination of modelling and optimization approach

Experimental studies have demonstrated differences in the intrinsic physiological responses between ON and OFF retinal ganglion cells (RGCs). OFF cells exhibit intrinsic spontaneous activity, subthreshold membrane potential oscillations, rebound excitation and burst firing. ON cells display none of the aforementioned intrinsic phenomena. Previous modeling studies [1, 2] showed how special properties of low-voltage-activated (T-type) calcium currents can explain the physiological differences between ON and OFF RGCs, while assuming that most of the other ion channel properties are similar. In our study, using a combination of computer simulations of single compartment, Hodgkin-Huxley type neurons and Bayesian optimisation, we optimised the leak reversal potential and all literature-reported ion channel conductance densities against experimental findings from mouse ON and OFF RGCs to estimate the potential contributions of other ion channels. Optimising the larger set of conductances suggested two distinct sets of parameters for ON and OFF cells (Table 1). In agreement with previous findings [1, 2], the low-voltage-activated calcium conductance (glva) is indeed higher in OFF than ON cells, but our results (Figure 1) suggested further that glva is the main contributor to the differences between ON and OFF cells. In addition, we found that the voltage-gated sodium channel conductance may be very different in ON and OFF cells, as also suggested in [2]. In addition, our analysis (not shown here) also suggests that mainly the fast inactivating sodium current, not the persistent sodium current, play a significant role in generating distinct properties in ON and OFF GCs. Overall, our single neuron model with optimised ion channel parameters was able to demonstrate a major dependence of ON and OFF cell specific intrinsic activity on the sodium and calcium currents.