Inhibition of brain 17β-estradiol synthesis by letrozole induces cognitive decline in male and female rats

Molecular and electrophysiological changes in the hippocampus and associated behavioral changes following 14 consecutive days of ICV-Letrozole administration. In untreated neurons, there is peripheral 17β-estradiol (E2, red circle) and hippocampal neurosteroids (E2, purple circle), and the cells show a spontaneous firing rate of about 8 spike per second or less recorded by in vivo single unit recording. In chronically letrozole-treated animals, hippocampal E2 synthesis was suppressed dramatically. Letrozole increased the hippocampal ERα and ERβ gene expression (green and yellow) and simultaneously decreased GPR30 gene expression (brown) in females. In addition, single unit recording showed a reduction in hippocampal pyramidal cell firing rates. In spite of peripheral E2 availability, letrozole-treated rats showed impaired spatial working memory, reduced novel object recognition memory, and heightened anxiety-like behavior. [Display omitted] •Letrozole was administered in rat brain lateral ventricles for 14 consecutive days.•Hippocampal E2 synthesis was suppressed dramatically by letrozole injection.•Letrozole induced detrimental cognitive effects in presence or absence of gonads.•Letrozole altered hippocampal ERα, ERβ and GPR30 gene expression.•Pyramidal neuronal firing rates decreased following letrozole administration. Hippocampal aromatase is responsible for local synthesis of 17β-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats. Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording. Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cogniti