Abstract
Depletion of microglia in the aged mouse brain is known to improve cognitive functions. However, even temporal ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-year-old) mice were treated with PLX3397 for 28 days, which reduced microglia numbers in the hippocampus to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling. This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribundaagglutinin-positive perineuronal nets (PNN) in the CA1 region of the hippocampus, it changed the fine structure of PNNs and elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 and postsynaptic PSD95 proteins at the excitatory synapses in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.