Early Life Inflammation Increases CA1 Pyramidal Neuron Excitability in a Sex and Age Dependent Manner through a Chloride Homeostasis Disruption

Abstract

Early life, systemic inflammation causes long-lasting changes in behavior. To unmask possible mechanisms associated with this phenomenon, we asked whether the intrinsic membrane properties in hippocampal neurons were altered as a consequence of early life inflammation. C57BL/6 mice were bred in-house and both male and female pups from multiple litters were injected with lipopolysaccharide (LPS; 100 μg/kg, i.p.) or vehicle at postnatal day (P)14, and kept until adolescence (P35–P45) or adulthood (P60–P70), when brain slices were prepared for whole-cell and perforated-patch recordings from CA1 hippocampal pyramidal neurons. In neurons of adult male mice pretreated with LPS, the number of action potentials elicited by depolarizing current pulses was significantly increased compared with control neurons, concomitant with increased input resistance, and a lower action potential threshold. Although these changes were not associated with changes in relevant sodium channel expression or differences in capacitance or dendritic architecture, they were linked to a mechanism involving intracellular chloride overload, revealed through a depolarized GABA reversal potential and increased expression of the chloride transporter, NKCC1. In contrast, no significant changes were observed in neurons of adult female mice pretreated with LPS, nor in adolescent mice of either sex. These data uncover a potential mechanism involving neonatal inflammation-induced plasticity in chloride homeostasis, which may contribute to early life inflammation-induced behavioral alterations.

SIGNIFICANCE STATEMENT Early life inflammation results in long-lasting changes in many aspects of adult physiology. In this paper we reveal that a brief exposure to early life peripheral inflammation with LPS increases excitability in hippocampal neurons in a sex- and age-dependent manner through a chloride homeostasis disruption. As this hyperexcitability was only seen in adult males, and not in adult females or adolescent animals of either sex, it raises the possibility of a hormonal interaction with early life inflammation. Furthermore, as neonatal inflammation is a normal feature of early life in most animals, as well as humans, these findings may be very important for the development of animal models of disease that more appropriately resemble the human condition.