ROLE OF ANDROGENS IN THE REGULATION OF CA1 NEURONAL MICROCIRCUITS AND OSCILLATIONS

Sex differences in cognition are linked to hormone signaling through nuclear receptors. In the hippocampus, excitatory (ENs) and inhibitory neurons (INs) form efficiently organized networks that generate oscillatory patterns essential for memory encoding and spatial navigation. Despite their critical role in normal hippocampal function, the impact of androgens on ENs and INs remains poorly understood.
We exploited single-cell RNA sequencing data from the Allen Brain dataset to study androgen receptor (AR) expression in different hippocampal neuronal populations. Although AR expression was higher in ENs (CA1>CA3>Dentate Gyrus), multiple IN subtypes also expressed AR, with marked sex differences. To determine how AR influences hippocampal network activity, we selectively knocked down AR expression from CA1 ENs and INs using the CRISPR/Cas9 technology. Local field potentials were recorded using 16-channel probes in head-restrained mice trained to run on a wheel. Knockdown of AR in CA1 ENs resulted in increased theta peak frequency and power, particularly during locomotion. Gamma peak frequency was unchanged, but power increased. In contrast, AR knockdown in Parvalbumin (PV) INs reduced theta power, while AR knockdown in somatostatin (SST) INs increased theta and gamma power, indicating cell-type-specific effects. These findings show that androgens regulate CA1 microcircuits and oscillations through multiple local neuronal types with potential implications for aging and other conditions associated with altered androgen signaling.