Sex-specific regulation of inhibition and network activity by local aromatase in the mouse hippocampus

Cognitive function relies on a balanced interplay between excitatory and inhibitory neurons (INs), but the impact of estradiol on IN function is not fully understood. Here, we characterize the regulation of hippocampal INs by aromatase, the enzyme responsible for estradiol synthesis, using a combination of molecular, genetic, functional and behavioral tools. The results show that CA1 parvalbumin-expressing INs (PV-INs) contribute to brain estradiol synthesis. Brain aromatase regulates synaptic inhibition through a mechanism that involves modification of perineuronal nets enwrapping PV-INs. In the female brain, aromatase modulates PV-INs activity, the dynamics of network oscillations and hippocampal-dependent memory. Aromatase regulation of PV-INs and inhibitory synapses is determined by the gonads and independent of sex chromosomes. These results suggest PV-INs are mediators of estrogenic regulation of behaviorally-relevant activity. Using a combination of molecular, genetic, functional and behavioural tools, this study describes the impact of brain synthesized estrogen in inhibitory neuronal function, network oscillations and hippocampal dependent memory.