Reactive astrocytes - comprehending when neurons play 4’33”

Abstract Homeostatic regulation is a powerful tool utilized by virtually all biological systems, brain included. Broadly speaking, each homeostatic process embodies two components: the sensing component, whereby a deviation is detected and quantified, and the effecting component that executes the homeostatic adjustment with the goal of alleviating the deviation. In the central nervous system, homeostatic plasticity has been suggested to play an important role in shaping the dynamics of single neurons and neuronal networks. However, existing “biophysical” models of homeostatic plasticity are exceedingly simplistic. These models usually describe the sensor component in terms of simple averaging over neuronal activity and offer no explanation of the relevant biochemical pathways. Here, we attempt to fill this gap in our understanding of homeostatic plasticity by proposing a biophysical framework to explain detection of prolonged synaptic inactivity that may occur in some scenarios of brain injury. We propose that sensing of, and response to, synaptic inactivity involves detection of the extracellular glutamate level and occurs via the activation of metabotropic glutamate receptors (mGluRs), while the inactivity-induced synthesis of one of the homeostatic plasticity effectors, tumor necrosis factor alpha (TNFα), serves as an effecting component of the system. This model can help to explain the experimental observations linking prolonged neuronal inactivity to TNFα signaling. Importantly, the proposed signaling scheme is not limited to mGluRs and astrocytes, but rather is potentially applicable to any cells expressing receptors that activate the relevant G protein units. The proposed signaling scheme is likely to be useful for developing pharmacological interventions targeting homeostatic plasticity pathways. Author summary Homeostatic regulation refers to the self-regulation ability of a system aimed at remaining in the same (or nearly the same) state. Homeostatic plasticity, a form of homeostatic regulation that arises in the context of neural dynamics, has been shown to shape neuronal and network dynamics by attempting to maintain physiological levels of neuronal activity in brain networks. Thus, it changes the excitation-inhibition balance in a network when sufficiently large and long-lasting deviations from physiological levels of activity are detected. However, the biophysical mechanisms of homeostatic plasticity and in particular those related to the ability to sense neuronal inactivity, remain elusive. We propose a feasible biophysical model of a homeostatic sensor, in which the sensing of inactivity depends on the presence and activation of G-protein-coupled receptors with different activation thresholds. In this model, the activation of the higher-threshold receptor suppresses the detection of inactivity, while the activation of the lower-threshold receptor promotes the detection of inactivity. The proposed model helps to explain a growing body of experimental data relating synaptic inactivity to production of homeostatic plasticity effectors such as tumor necrosis factor alpha. Although we consider a specific case study of metabotropic glutamate receptors on astrocytes, the model conclusions are likely to be applicable to any cells expressing receptors that activate the relevant G protein units.