Abstract
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.
Highlights
Cooperative molecular interactions are ubiquitous in biology and guide cellular processes from sensing to memory formation (Bray et al, 1998; Burrill and Silver, 2010)
Our central observation is that the mutually enhancing nature of cooperative gating favors joint opening and closing of channels, and, more importantly, results in a hysteresis of their gating behavior. We demonstrate that such cooperative channels - when arranged in clusters and located in membranes with ‘normal’ independent conductances that mediate spiking - can induce graded persistent neural activity: spiking that persists after transient suprathreshold depolarization and represents successive inputs with increasing persistent firing rates
Despite a large body of evidence for cooperative interactions between channels pivotal to the nervous system (Iwasa et al, 1986; Dekker and Yellen, 2006; Kim et al, 2014; Choi, 2014; Dixon et al, 2015; Moreno et al, 2016; Clatot et al, 2017), it is unknown which function coupled channels have for neural dynamics and computation
Summary
Cooperative molecular interactions are ubiquitous in biology and guide cellular processes from sensing to memory formation (Bray et al, 1998; Burrill and Silver, 2010). Cardiac alternans, a pathological condition of unstable heart contractions, has been linked to strong degrees of coupling among cooperative calcium channels (Sato et al, 2018) These studies demonstrate that cooperative channels can significantly alter cellular firing properties with a range of effects from advantageous to pathological depending on the interplay with other currents in the cell. Our central observation is that the mutually enhancing nature of cooperative gating favors joint opening and closing of channels, and, more importantly, results in a hysteresis of their gating behavior We demonstrate that such cooperative channels - when arranged in clusters and located in membranes with ‘normal’ independent conductances that mediate spiking - can induce graded persistent neural activity: spiking that persists after transient suprathreshold depolarization and represents successive inputs with increasing persistent firing rates. We use the dynamic clamp technique to experimentally endow perirhinal cortex neurons with ‘virtual’ cooperative ion channels and show that stable persistent activity can be robustly induced, rendering ion channel cooperativity an efficient and plausible mechanism for cellular voltage memory
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