Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats

Abstract

The role of microglia in mediating age‐related changes in cognition and hippocampal synaptic function was examined by microglial depletion and replenishment using PLX3397. We observed age‐related differences in microglial number and morphology, as well as increased Iba‐1 expression, indicating microglial activation. PLX3397 treatment decreased microglial number, with aged rats exhibiting the lowest density. Young rats exhibited increased expression of pro‐inflammatory cytokines during depletion and repopulation and maintenance of Iba‐1 levels despite reduced microglial number. For aged rats, several cytokines increased with depletion and recovered during repopulation; however, aged rats did not fully recover microglial cell number or Iba‐1 expression during repopulation, with a recovery comparable to young control levels rather than aged controls. Hippocampal CA3–CA1 synaptic transmission was impaired with age, and microglial depletion was associated with decreased total synaptic transmission in young and aged rats. A robust decline in N‐methyl‐d‐aspartate‐receptor‐mediated synaptic transmission arose in young depleted rats specifically. Microglial replenishment normalized depletion‐induced synaptic function to control levels; however, recovery of aged animals did not mirror young. Microglial depletion was associated with decreased context‐object discrimination memory in both age groups, which recovered with microglial repopulation. Aged rats displayed impaired contextual and cued fear memory, and microglial replenishment did not recover their memory to the level of young. The current study indicates that cognitive function and synaptic transmission benefit from the support of aged microglia and are hindered by removal of these cells. Replenishment of microglia in aging did not ameliorate age‐related cognitive impairments or senescent synaptic function.

Microglia control glutamatergic synapses in the adult mouse hippocampus

“…A weakening of hippocampal glutamatergic transmission after microglia depletion was recently observed by Yegla et al (2021). Consistently, it was reported that upon microglia contact with synapses increases synaptic activity and neuronal synchronization in the primary motor cortex (Akiyoshi et al, 2018).…”

Age-related immune alterations and cerebrovascular inflammation

“…Despite the dysregulated state of aged microglia, this experiment suggests that aged microglia have some beneficial effects during the acute phase of ischemic stroke. Similar findings have been reported in aged rats, where cognitive function and synaptic transmission benefit from the support of aged microglia, and removal of these cells was deleterious [ 154 ]. However, the chronic effects of microglia depletion and repopulation on cognition and stroke repair remain to be investigated (Fig.…”

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

“…In this study, the repopulation efficiency upon PLX3397 (i.e., a pharmacological inhibitor of CSF1R) treatment was also estimated. Aged rats did not fully recover microglial cells number during repopulation as well as these cells express more cytokines than young microglia (Yegla et al, 2021). The study of young and aged prefrontal cortices of rats did not reveal any difference in terms of cell number, while it has been observed a shift in microglia volume in aged animals (Chan et al, 2018).…”