Long-lasting effects of elevated neonatal leptin on rat hippocampal function, synaptic proteins and NMDA receptor subunits.

The high circulating levels of leptin in neonatal rodents do not seem to be regulating energy balance at this age, but rather may play an important role for brain development. We tested the hypothesis that high neonatal leptin levels modify hippocampal function and production of synaptic proteins with possible long-term consequences on long-term potentiation (LTP) in adulthood. We first showed that in postnatal day (PND) 10 neonates, acute leptin treatment functionally activated leptin receptors (ObR) in the CA1 and DG regions of the hippocampus through the induction of phosphoERK1/2, but not phosphoSTAT3 protein although both phospho-proteins were induced in the arcuate nucleus. We next examined whether chronic leptin administration (3 mg/kg BW, intraperitoneally) during the first 2 weeks of life (postnatal day, PND 2-14) produces a functional signal in the hippocampus that alters the expression of NMDA receptor subunits (NR1, NR2A, NR2B), synaptic proteins and LTP in the short and long-term. In PND 10 as in adults (PND 70) rats, chronic leptin treatment increased NR1 expression in the hippocampus while reducing NR2B protein levels. Elevated hippocampal concentrations of synapsin2A and synaptophysin were detected during leptin treatment on PND 10 suggesting increased neurotransmitter release. In adults, only SNAP-25 expression was increased after neonatal leptin treatment. LTP was reduced dramatically by leptin treatment in preweaning rats although the changes did not persist until adulthood. Elevated exposure to leptin during a critical period of neonatal hippocampal development might serve to enhance NMDA-dependent functions other than LTP and have important effects on synaptogenesis and neurotransmitter release.