Sex differences in the nicotinic excitation of principal neurons within the developing hippocampal formation

The hippocampal formation (HF) plays an important role to facilitate higher order cognitive functions. Cholinergic activation of heteromeric nicotinic acetylcholine receptors (nAChRs) within the HF is critical for the normal development of principal neurons within this brain region. However, previous research investigating the expression and function of heteromeric nAChRs in principal neurons of the HF is limited to males or does not differentiate between the sexes. We used whole-cell electrophysiology to show that principal neurons in the CA1 region of the female mouse HF are excited by heteromeric nAChRs throughout postnatal development, with the greatest response occurring during the first two weeks of postnatal life. Excitability responses to heteromeric nAChR stimulation were also found in principal neurons in the CA3, dentate gyrus, subiculum, and entorhinal cortex layer VI (ECVI) of young postnatal female HF. A direct comparison between male and female mice found that principal neurons in ECVI display greater heteromeric nicotinic passive and active excitability responses in females. This sex difference is likely influenced by the generally more excitable nature of ECVI neurons from female mice, which display a higher resting membrane potential, greater input resistance, and smaller afterhyperpolarization potential of medium duration (mAHP). These findings demonstrate that heteromeric nicotinic excitation of ECVI neurons differs between male and female mice during a period of major circuitry development within the HF, which may have mechanistic implications for known sex differences in the development and function of this cognitive brain region.