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.
Highlights
Neurons continuously modify their synaptic and intrinsic membrane properties in response to variations in their environment
A central role has been attributed to protein kinase and phosphatase (KP) cycles in these networks because strong experimental evidence indicates that they exert a critical control over the induction [5,6,7] and maintenance [8,9] of activity-dependent plastic modifications
Experimental studies have identified numerous molecules that are necessary for the induction and the maintenance of plastic modifications, including activitydependent kinase and phosphatase cycles
Summary
Neurons continuously modify their synaptic and intrinsic membrane properties in response to variations in their environment (e.g., ionic conditions, neuromodulatory influences, and synaptic input). These adaptive modifications are set up rapidly, can be memorized from seconds to years, and subserve essential neuronal functions such as homeostatic regulation and information storage. Activity-dependent modifications implicate complex networks of densely interconnected signaling pathways and modulation of gene expression [2,3,4]. The question stands whether KP cycles constitute the genuine organization that is mechanistically responsible for memory formation, or whether information storage requires the consideration of larger interaction networks or gene regulation [2,3,4].
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