Interplay between biochemical processes and network properties generates neuronal up and down states at the tripartite synapse.

Abstract

Neuronal up and down states have long been known to exist both in vitro and in vivo. A variety of functions and mechanisms have been proposed for their generation, but there has not been a clear connection between the functions and mechanisms. We explore the potential contribution of cellular-level biochemistry to the network-level mechanisms thought to underlie the generation of up and down states. We develop a neurochemical model of a single tripartite synapse, assumed to be within a network of similar tripartite synapses, to investigate possible function-mechanism links for the appearance of up and down states. We characterize the behavior of our model in different regions of parameter space and show that resource limitation at the tripartite synapse affects its ability to faithfully transmit input signals, leading to extinction-down states. Recovery of resources allows for "reignition" into up states. The tripartite synapse exhibits distinctive "regimes" of operation depending on whether ATP, neurotransmitter (glutamate), both, or neither, is limiting. Our model qualitatively matches the behavior of six disparate experimental systems, including both in vitro and in vivo models, without changing any model parameters except those related to the experimental conditions. We also explore the effects of varying different critical parameters within the model. Here we show that availability of energy, represented by ATP, and glutamate for neurotransmission at the cellular level are intimately related, and are capable of promoting state transitions at the network level as ignition and extinction phenomena. Our model is complementary to existing models of neuronal up and down states in that it focuses on cellular-level dynamics while still retaining essential network-level processes. Our model predicts the existence of a "final common pathway" of behavior at the tripartite synapse arising from scarcity of resources and may explain use dependence in the phenomenon of "local sleep." Ultimately, sleeplike behavior may be a fundamental property of networks of tripartite synapses.