The Role of Estrogen in Regulating Microglia, Perineuronal Nets, and Cognition

Abstract

The importance of the neurosteroid estrogen in the dorsal CA1 (dCA1) of the mouse hippocampus for promoting proper spatial memory has been well-established. Microglia, the brain’s resident immune cells, interact with parvalbumin-positive interneurons (PV+ interneurons) and the perineuronal nets (PNNs) that enwrap and stabilize these PV+ interneurons to maintain proper excitatory/inhibitory balance and modulate neuroplasticity. However, less is known about the effects of low estrogen states in the healthy adult mouse dCA1 on microglia and the ways in which microglia interact with PNNs and the PV+ interneurons they surround. Here, we use the aromatase inhibitor letrozole (LET) to globally induce low estrogen states in adult female mice. We use the novel object recognition (NOR) task to assess dCA1-dependent object memory, demonstrating that 10-day LET results in object memory impairment. We also performed immunohistochemistry (IHC) to stain PNNs for the PNN component aggrecan (ACAN) and histochemistry (HC) to stain PNNs with Wisteria floribunda agglutinin (WFA), as well as to stain microglia for ionized calcium-binding adapter molecule 1 (Iba1). We find that 10-day LET treatment increases PNN intensity measured by ACAN, with no effect on other PNN hole characteristics evaluated when stained for ACAN or WFA. Furthermore, 24-hour LET treatment did not alter microglial intensity or microglial cell body area, although both 24-hour and 10-day LET treatment decreased microglial engulfment of PNNs. These results can inform mechanistic and clinical understandings of certain memory impairments that are estrogen- dependent, potentially benefitting therapies for alleviating memory impairment.