INTRINSIC PROPERTIES OF CA1 PYRAMIDAL CELLS ARE SET BY SEX HORMONES IN ORGANOTYPIC HIPPOCAMPAL SLICES FROM MALE AND FEMALE MICE

Perinatal hormone exposure is essential for the sexual differentiation of the brain. Interestingly, perinatal testosterone exposure has been linked to an increased susceptibility to Autism Spectrum Disorder (ASD), which may contribute to the observed male:female bias in ASD of ~4:1. However, it is currently poorly understood how testosterone and its metabolites shape neuronal development and how this could introduce or enhance vulnerability to ASD.
The metabolization of testosterone can be roughly split up into two different pathways: androgenic (consisting of testosterone and its metabolite dihydrotestosterone) and estrogenic (consisting of testosterone’s metabolite estradiol). To investigate the effect of these two different pathways, we exposed DIV11-16 organotypic hippocampal slices for 24 hours to either testosterone or testosterone combined with letrozole, which blocks conversion of testosterone to estradiol. We performed whole-cell patch clamp electrophysiology on CA1 pyramidal cells to record firing properties, afterhyperpolarization after action potentials and voltage sag currents (reflecting the opening of HCN channels).
Our preliminary data suggest that HCN channel activity and afterhyperpolarization duration are altered by sex hormones in both sexes, whereas firing properties are not. Current efforts are underway to confirm these observations and to directly test the role of estradiol in regulating intrinsic properties of CA1 pyramidal cells. Our first data suggests that some intrinsic electrophysiological properties are regulated exclusively by testosterone in males and exclusively by estradiol in females. Our experiments will provide an important step in understanding how hormone exposure affects neuronal network development and how this may increase susceptibility to ASD.