Tumor necrosis factor alpha maintains denervation-induced homeostatic synaptic plasticity of mouse dentate granule cells

Neurons which lose part of their input respond with a compensatory increase in excitatory synaptic strength. This observation is of particular interest in the context of neurological diseases, which are accompanied by the loss of neurons and subsequent denervation of connected brain regions. However, while the cellular and molecular mechanisms of pharmacologically induced homeostatic synaptic plasticity have been identified to a certain degree, denervation-induced homeostatic synaptic plasticity remains not well understood. Here, we employed the entorhinal denervation in vitro model to study the role of tumor necrosis factor alpha (TNF alpha) on changes in excitatory synaptic strength of mouse dentate granule cells following partial deafferentation. Our experiments disclose that TNF alpha is required for the maintenance of a compensatory increase in excitatory synaptic strength at 34 days post lesion (dpl), but not for the induction of synaptic scaling at 12 dpl. Furthermore, laser capture microdissection combined with quantitative PCR demonstrates an increase in TNF alpha-mRNA levels in the denervated zone, which is consistent with our previous finding on a local, i.e., layer-specific increase in excitatory synaptic strength at 34 dpl. Immunostainings for the glial fibrillary acidic protein and TNF alpha suggest that astrocytes are a source of TNF alpha in our experimental setting. We conclude that TNF alpha-signaling is a major regulatory system that aims at maintaining the homeostatic synaptic response of denervated neurons.