Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory

Across biological systems, cooperativity between proteins enables fast actions, supra-linear responses, and long-lasting molecular switches. In the nervous system, however, the function of cooperative interactions between voltage-dependent ionic channels remains largely unknown. Based on mathematical modeling, we here demonstrate that clusters of strongly cooperative ion channels can plausibly form bistable conductances. Consequently, clusters are permanently switched on by neuronal spiking, switched off by strong hyperpolarization, and remain in their state for seconds after stimulation. The resulting short-term memory of the membrane potential allows to generate persistent firing when clusters of cooperative channels are present together with non-cooperative spike-generating conductances. Dynamic clamp experiments in rodent cortical neurons confirm that channel cooperativity can robustly induce graded persistent activity – a single-cell based, multistable mnemonic firing mode experimentally observed in several brain regions. We therefore propose that ion channel cooperativity constitutes an efficient cell-intrinsic implementation for short-term memories at the voltage level.

With the dynamic clamp experiment, we aimed at a further test of the shortterm memory mechanism by cooperative ion channels. After a series of test recordings to establish the dynamic clamp software, we recorded three neurons from layer II of the perirhinal cortex. All three cells exhibited graded persistent activity in the presence of the emulated cooperative channels. We see this as sufficient support for our theoretical prediction that the mechanisms is generic and robust enough to work in a biological neuron.

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We did not perform a statistical analysis. However, we report which pulse protocols we used and how often we observed persistent activity in each one of them, see material and methods section "Analysis".
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