Maternal care modulates chloride cotransporter development during inhibitory circuit maturation in the piriform cortex

Early postnatal development is a sensitive period for inhibitory circuit maturation, marked by a shift in GABAergic signaling from depolarizing to hyperpolarizing actions. This transition depends on chloride homeostasis, which is regulated by the potassium- chloride cotransporter 2 (KCC2) and the sodium-potassium-chloride cotransporter 1 (NKCC1). While these cotransporters are known to drive inhibitory development, little is understood about how early caregiving experience influences their trajectories in brain regions critical for attachment learning. Here, we examined the developmental profiles of KCC2 and NKCC1 in the piriform cortex of male and female rats from postnatal (P) day 5 to 22 and assessed their sensitivity to altered maternal care using the limited bedding and nesting (LBN) paradigm from P2 to P9. Both transporters progressively increased protein levels toward adult-like levels, with sex-specific regulation observed at the mRNA level. At P15, LBN reduced KCC2 and NKCC1 protein levels in a region- and sex- dependent manner. To evaluate the functional consequences of these changes at the neural level, we implemented a Hodgkin-Huxley computational model with dynamic ion concentration parameters, which were parameterized using our experimental data. Simulation revealed that cotransporter profiles induced by LBN altered the chloride equilibrium, changing the impact of GABAergic input on neuronal excitability. This integrative approach offers a mechanistic insight into how early caregiving experiences affect chloride transporter regulation, with consequences for synaptic signaling and neuronal activity, ultimately contributing to the development of inhibitory circuits.