With severe injury or disease, microglia become chronically activated and damage 
the local brain environment, likely contributing to cognitive decline. We 
previously discovered that microglia are dependent on colony-stimulating factor 
1 receptor (CSF1R) signaling for survival in the healthy adult brain, and we 
have exploited this dependence to determine whether such activated microglia 
contribute deleteriously to functional recovery following a neuronal lesion. 
Here, we induced a hippocampal lesion in mice for 25 d via neuronal expression 
of diphtheria toxin A-chain, producing both a neuroinflammatory reaction and 
behavioral alterations. Following the 25 d lesion, we administered PLX3397, a 
CSF1R inhibitor, for 30 d to eliminate microglia. This post-lesion treatment 
paradigm improved functional recovery on elevated plus maze and Morris water 
maze, concomitant with reductions in elevated proinflammatory molecules, as well 
as normalization of lesion-induced alterations in synaptophysin and PSD-95. 
Further exploration of the effects of microglia on synapses in a second cohort 
of mice revealed that dendritic spine densities are increased with long-term 
microglial elimination, providing evidence that microglia shape the synaptic 
landscape in the adult mouse brain. Furthermore, in these same animals, we 
determined that microglia play a protective role during lesioning, whereby 
neuronal loss was potentiated in the absence of these cells. Collectively, we 
demonstrate that microglia exert beneficial effects during a diphtheria 
toxin-induced neuronal lesion, but impede recovery following insult.
SIGNIFICANCE STATEMENT: It remains unknown to what degree, and by what 
mechanisms, chronically activated microglia contribute to cognitive deficits 
associated with brain insults. We induced a genetic neuronal lesion in mice for 
25 d and found activated microglia to increase inflammation, alter synaptic 
surrogates, and impede behavioral recovery. These lesion-associated deficits 
were ameliorated with subsequent microglial elimination, underscoring the 
importance of developing therapeutics aimed at eliminating/modulating chronic 
microglial activation. Additionally, we found long-term microglial depletion 
globally increases dendritic spines by ∼35% in the adult brain, indicating that 
microglia continue to sculpt the synaptic landscape in the postdevelopmental 
brain under homeostatic conditions. Microglial manipulation can therefore be 
used to investigate the utility of increasing dendritic spine numbers in 
postnatal conditions displaying synaptic aberrations.