Reactive astrocytes - comprehending when neurons play 4'33"

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 9biophysical9 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.