CHEMOGENETIC ACTIVATION OF GQ IN MICROGLIA REDUCES NEURONAL EXCITABILITY AND PROTECTS AGAINST EXCITOTOXITY

Activation of microglia by inflammation or chronic disease has profound effects on neurons and synapses. The details of this communication between the immune system and the brain are under active investigation. Common strategies to experimentally activate microglia, such as lipopolysaccharide injection, primarily activate the peripheral immune system, triggering a complex and protracted response of the whole organism. In order to activate microglia selectively and with precise timing, we used chemogenetic activation of a Gq-DREADD expressed exclusively in microglia. This approach allowed us to study the effect of microglia on hippocampal synaptic function without the risk of direct neuronal or astrocytic activation.
Chronic Gq-DREADD activation in microglia decreased the spine density of excitatory synapses on CA1 pyramidal cell dendrites and led to a strong decrease in action potential firing during current injections. We also observed lengthening of the axonal initial segment, which is a common homeostatic response to low activity. In vivo, activation of Gq-DREADD significantly reduced long-term potentiation and remote memory. We utilize this model of targeted microglial manipulation to understand the role of microglia in stroke. We report decreased phagocytic activity of microglia and increased neuronal survival after oxygen-glucose-deprivation (OGD). Taken together, our findings show that Gq-activated microglia reduce neuronal excitability and connectivity, which we hypothesize makes neurons more resilient to ischemic insult.