Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus

Abstract

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.

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

“…Persistent inflammation caused by age and disease elicits chronic activation of microglia that can reshape the synaptic landscape and compromise cognition (24). Mice depleted of microglia retain higher levels of dendritic spine density and suffer few if any adverse neurocognitive outcomes (25). To ascertain the potential functional consequences of MV-mediated reductions in activated microglia, experimental cohorts were subjected to Golgi staining for the structural assessment of GCL neurons in the DG of the hippocampus.…”

Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

“…The Yin and Yang of CSF-1R targeting in neurodegeneration (Figure 4) is illustrated by the study of Rice et al [85], who examined the effects of inhibition of CSF-1R signaling on recovery from hippocampal lesions. Inhibition of CSF-1R signaling post-lesioning improved neuronal survival and functional recovery, whereas inhibition of CSF-1R signaling during the lesioning period increased neuronal loss.…”

Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury

“…For example, a recent study induced hippocampal lesion using the CaM/Tet-DT A model and subsequently eliminated microglia using CSF1R antagonism [55, 56]. Loss of microglia increased hippocampal neuron death compared to controls, suggesting a protective role for microglia acutely.…”