Postnatal Development of Chloride Cotransporters in the Piriform Cortex and Its Modulation by Early Maternal Care

Early postnatal development is a sensitive period for inhibitory maturation, during which GABAergic signaling shifts from depolarizing to hyperpolarizing as a function of the chloride cotransporters KCC2 and NKCC1. Although these cotransporters are key to inhibitory development, little is known about how early caregiving influences their maturation in cortical circuits supporting attachment learning. We characterized KCC2 and NKCC1 expression in the piriform cortex (PC) of male and female rats from postnatal (P) Day 5 to 22 and assessed their sensitivity to altered caregiving using the limited bedding and nesting (LBN) paradigm (P2-P9). Both cotransporters showed robust postnatal protein upregulation, with sex-specific transcriptional differences for KCC2. At P15, LBN induced sex- and region-dependent changes. KCC2 transcription decreased in the anterior PC of males but increased in females in the posterior PC. NKCC1 protein was reduced in both sexes with distinct anterior-posterior patterns. Using a single-neuron Hodgkin-Huxley model with dynamic ion concentrations incorporating the measured cotransporter profiles, simulations indicated that these differences were sufficient to modify chloride homeostasis and shift GABAergic control of excitability. This multiscale approach links early alterations in caregiving to predicted functional consequences for inhibitory maturation in the PC.