Neuroinflammatory and behavioral effects of inadequate perisynaptic astrocyte glycogen utilization

Several findings suggest that the brain energy demand is mostly localized at the synapses, and glycogen in the perisynaptic astrocytic endfeet serves as the main actor that matches the synaptic energy supply and demand. In this study, we hypothesized that disruption of synaptic energy delivery from glycogen would cause metabolic stress in the synapse, which could trigger neuroinflammation and lead to changes in the behavioral phenotype. For this purpose, glycogenolysis inhibitor "DAB" was bilaterally injected into the dorsal hippocampus region and selected brain regions were evaluated in terms of microglial activation findings. Unlike the control group, DAB group showed widespread microglial activation in the ventral hippocampus, amygdalar region and entorhinal cortical area, which are located far from the injection site. In order to observe the behavioral output of this neuroinflammatory phenotype, mice were subjected to a group of tests evaluating depression-like and anxiety-like behavior on the first, third and fifth days after the injections. Contrary to our hypothesis, no significant depressogenic or anxiogenic effect of DAB was observed. On the other hand, it is noteworthy that the sucrose preference and social interaction index were higher in the DAB group, where we expected to observe anhedonia-like behavior. All these findings indicate that inhibition of hippocampal glycogenolysis may trigger widespread microglial activation in the brain and this effect may lead to changes in the behavioral phenotype in favor of hedonia.