Sex Differences in The Regulation of Neuron Excitability within Layer VI of The Mouse Entorhinal Cortex

Abstract

The entorhinal cortex (EC) comprises part of the hippocampal formation and plays an important role to facilitate cognitive processes including learning and memory. The EC may be divided into six cellular layers that have unique neuron populations and communication targets. In particular, the sixth EC layer (ECVI) receives afferent signals from the hippocampus and contains glutamatergic pyramidal neurons that transmit efferent signals to other regions of the brain. Although several studies have characterized basic electrophysiological properties of neurons within the more superficial layers of the EC, detailed characteristics of pyramidal neurons within ECVI are not well understood. We recently identified a profound sex difference in the excitability of ECVI neurons during early postnatal life, in that neurons from female mice are more excitable than neurons from male mice. While this sex difference correlates with a smaller afterhyperpolarization of medium duration (mAHP) in female ECVI neurons, the precise mechanisms have not been determined. This study aims to determine the contribution of small-conductance calcium-activated potassium (SK) channels toward sex differences in ECVI neuron excitability in young postnatal (P5-10) and adult (P80-120) mice. Contrary to our previous finding in young postnatal mice, we observed no baseline sex differences in adult mice for passive electrophysiological properties such as resting membrane potential and membrane resistance, or for active electrophysiological properties such as input-output responses or mAHP magnitude. The SK channel blocker apamin increased input resistance and decreased rheobase in both sexes. However, the ability of apamin to decrease mAHP magnitude and increase input-output excitability responses was far greater in male than in females. Ongoing experiments aim to determine the effect of SK channel blockade on neuronal excitability in young postnatal mice. These novel findings demonstrate that SK channels play a greater role in regulating ECVI neuron excitability in male mice than in female mice. This knowledge advances our understanding of neuron function within the hippocampal formation and mechanisms underlying potential sex differences in hippocampal-dependent cognitive functions.