Stimulus statistics and HCN current mediated resonance sets the scale of input-output mapping in Stellate cells of the Medial Entorhinal Cortex

Abstract

The functional significance of the computations performed by Stellate cells of the Medial Entorhinal Cortex, proven time and again, makes them insightful, yet intriguing. The gradients of the intrinsic properties of these cells, aligned to the actual grid cell spacing gradients, have encouraged many thoughtful experiments. A long sought question in the stellate cell literature is thus the one seeking mechanistic implications for these correlates. The intrinsic dynamics of these cells have been tested previously in this light, primarily focusing on their spectral characteristics. However, the resonance phenomenon underlying these dynamics has not received the attention it deserves, and its potency under the in-vivo high conductance states to influence the input-output mapping remains to be estimated. In this light, we analysed the signal gain of stellate cells in the presence of in-vivo like fluctuating conductance based synaptic inputs injected through the Dynamic clamp, in rat brain slices. We observed a consistent, HCN current sensitive, theta frequency peak in signal gain, indicating that the HCN current mediated resonance mechanisms are functional even under a heavy input barrage. Next, we tested the effects of an array of input statistics on this signal gain and observed it to be mostly unaffected by the input strength, but relatively susceptible to the input kinetics. Additionally, as a possible reflection of the underlying signal gain, we observed a significant theta modulation of inputs by HCN current, the extent of which was found to be influenced by the excitatory, but not inhibitory synaptic kinetics. Surprisingly, a corresponding modulation in the gamma frequencies was also observed for the firing rate response, wherein the signal gain in gamma frequencies was found to be higher in the presence of HCN, which also coincided with increased occurrence of bursts A computational model with HCN-persistent sodium channels with similar simulated in vivo conditions could reproduce the experimental results, additionally suggesting the strength of inhibition and the kinetics of excitation as the input statistic based alternate resonance mechanisms which can operate independent of HCN. Our results thus suggest frequency dependent gain as an appropriate measure for analysing the input-output mapping in the stellate cells, and point out the mechanisms via which the HCN currents and input statistics can interact and determine the scaling of responses in these cells.