Project Details
Projekt
Elucidating the role of activated microglia in sculpting neuronal circuits after respiratory viral infections
Applicants
Dr. Shirin Hosseini; Professor Dr. Martin Korte
Subject Area
Experimental Models for the Understanding of Nervous System Diseases
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500260735
Various environmental factors, including viral infections, modulate microglial function, leading to pathological remodeling of synapses that may culminate in CNS dysfunction. The multifaceted microglial activation that can be triggered by CNS infection or strong peripheral immune stimulation requires peripheral and local cues. In the context of neuroinflammation, microglia, together with peripheral immune cells invading the brain, can promote pathological synapse loss. It has been previously shown that activated microglia triggered by neurotropic viral infections engulf synaptic terminals via an interferon-dependent mechanism and/or complement components. Yet, it remains to be determined to what extent viral infection influences microglia diversity leading to pathological alterations in synapse remodeling by specialized microglia. Recently, we have shown that sustained microglial activation induced by influenza A virus (IAV) infection with both non-neurotropic and neurotropic strains is indeed associated with synapse loss, impaired synaptic plasticity, cognitive decline, and local secretion of IFN-γ and CCL2 in the hippocampus, which may even last longer in aged mice. It is not yet known which peripheral and central signals trigger synaptic pruning by microglia during IAV infection. Other viruses have been shown to dysregulate the interplay between microglia and IFN-γ-producing T cells as trigger of phagocytosis of neuronal synapses leading to cognitive impairment. Therefore, the first part of this proposal will highlight the potential role of T cells as peripheral drivers of synaptic pruning by microglia via IFN-γ signaling and CCL2 expression as local cues or instructive signals recruiting microglia to specific synapses. While studies on microglia-mediated synaptic pruning focused so far on excitatory synapses a specific GABA-sensitive microglia population was identified recently during postnatal development responsible for pruning of inhibitory synapses. Abnormal synaptic inputs may alter the neuronal excitation/inhibition ratio, leading to seizures and a decline in intellectual and cognitive performance, as observed in patients after various influenza outbreaks. Therefore, the second part examines the impact of IAV infection on the functional diversity of microglia potentially responsible for a selective pruning of excitatory (glutamate-receptive microglia) versus inhibitory (GABA-receptive microglia) synapses, which may lead to an imbalance of excitatory and inhibitory neuronal activity (E/I imbalance). The understanding of the basis of IAV-induced microglia diversity will be further expanded using a humanized 3D culture system to provide further insights into the etiology of many neurological diseases that may be triggered by common viral infections and reveal new therapeutic strategies.
DFG Programme
Priority Programmes
