A New Principle for Information Storage in an Enzymatic Pathway Model

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Abstract
Strong experimental evidence indicates that protein kinase and phosphatase (KP) cycles are critical to both the induction and maintenance of activity-dependent modifications in neurons. However, their contribution to information storage remains controversial, despite impressive modeling efforts. For instance, plasticity models based on KP cycles do not account for the maintenance of plastic modifications. Moreover, bistable KP cycle models that display memory fail to capture essential features of information storage: rapid onset, bidirectional control, graded amplitude, and finite lifetimes. Here, we show in a biophysical model that upstream activation of KP cycles, a ubiquitous mechanism, is sufficient to provide information storage with realistic induction and maintenance properties: plastic modifications are rapid, bidirectional, and graded, with finite lifetimes that are compatible with animal and human memory. The maintenance of plastic modifications relies on negligible reaction rates in basal conditions and thus depends on enzyme nonlinearity and activation properties of the activity-dependent KP cycle. Moreover, we show that information coding and memory maintenance are robust to stochastic fluctuations inherent to the molecular nature of activity-dependent KP cycle operation. This model provides a new principle for information storage where plasticity and memory emerge from a single dynamic process whose rate is controlled by neuronal activity. This principle strongly departs from the long-standing view that memory reflects stable steady states in biological systems, and offers a new perspective on memory in animals and humans. It is now widely recognized that learning and memory rely on activity-dependent plastic modifications of the synaptic and intrinsic properties of individual neurons. Experimental studies have identified numerous molecules that are necessary for the induction and the maintenance of plastic modifications, including activity-dependent kinase and phosphatase (aKP) cycles. In contrast, the mechanisms that govern information storage in neurons remain obscure. Prevailing theoretical models either account for the rapid onset (models of plasticity) or for the protracted maintenance (models of memory) of plastic modifications, but have failed to embody both properties. We show in a biophysical model that the ubiquitous upstream activation of aKP cycles by neuronal activity is sufficient to generate information storage that combines rapid induction and maintenance with lifetimes compatible with animal and human memory. Moreover, aKP cycles exhibit essential information storage properties consistent with experimental data, including bidirectional plasticity, graded memory, and robustness to stochastic molecular fluctuations. The aKP model offers a realistic unified framework in which cellular plasticity and memory can be interpreted as two modes of a single process where dynamics depends on neuronal activity. This new principle is dynamic in essence and challenges the widespread idea that memory reflects stability in biological systems.