Estradiol effects on astrocytic aquaporin 4 and glutamate transporter 1 expression contribute to shifts in brain dynamics supporting spatial working memory.

Estrogenic effects on astrocytes improve glutamate recycling and water homeostasis for neuroprotection in pathology. Estrogens also enhance spatial learning and memory. The current study looked at the effect of 17β-estradiol (E2) on astrocytic glutamate transporter 1 (GLT-1) and aquaporin 4 (AQP4) in the prelimbic cortex (PrL) and dorsal hippocampus (dHC), areas active in spatial (allocentric) working memory in comparison to dorsolateral striatum (dlStr) which is involved in response or egocentric learning. Ovariectomized, female, Long Evans rats received 0, 4.5 µg/kg, or 45 µg/kg of E2 in a sesame oil vehicle 24 and 48 h prior to a delayed spontaneous alternation task (dSA). In line with previous research dSA performance significantly improved with administration of E2 as compared to sesame oil vehicle. AQP4 and GLT-1 levels were brain area specific and E2 enhanced AQP4 and GLT-1 in brain areas associated with spatial working memory (PrL and dHC) as compared to dlStr. Additionally, AQP4 was found to have the highest density in the unmyelinated axon rich hilus while GLT-1 showed the highest density in the synaptically dense molecular layer. However, AQP4 density in the stratum radiatum was similar to the hilus after dSA, potentially supporting dynamic changes in AQP4 response to natural cognitive activity. Hilar and prelimbic AQP4 area stained was also negatively correlated with performance on the dSA, which supports the theory of increased polarity of AQP4 with healthy cognitive function. These data suggest astrocytic water and glutamate homeostasis shift with high levels of estrogens to support spatial strategies.