NMDA receptor subunit composition determines the polarity of leptin-induced synaptic plasticity

Leptin is a hormone that crosses the blood-brain barrier and regulates numerous CNS functions. The hippocampus in particular is an important site for leptin action. Indeed, leptin markedly influences excitatory synaptic transmission and synaptic plasticity in this brain region. Recent studies indicate that leptin modulation of hippocampal excitatory synaptic transmission is age-dependent however the cellular basis for this is unclear. Here we show that early in development leptin evokes a transient (P11–18) or persistent (P5–8) depression of synaptic transmission, whereas leptin evokes a long lasting increase (LTP) in synaptic strength in adulthood. The synaptic depressions induced by leptin required activation of NMDA receptor GluN2B subunits and the ERK signalling cascade. Conversely, leptin-induced LTP in adult was mediated by GluN2A subunits and involved PI 3-kinase dependent signalling. In addition, low-frequency stimulus (LFS)-evoked LTD occluded the persistent effects of leptin at P5–8 and vice versa. Similarly, synaptically-induced LTP occluded the persistent increase in synaptic transmission induced by leptin, indicating that similar expression mechanisms underlie leptin-induced LTD and LFS-induced LTD at P5–8, and leptin-induced LTP and HFS-induced LTP in adult. These findings have important implications for the role of leptin in hippocampal synaptic function during early neuronal development and in aging.

► We have studied leptin regulation of hippocampal excitatory synaptic transmission.
► Early in development leptin induces LTD of synaptic transmission.
► In adult leptin evokes a persistent increase in hippocampal synaptic efficacy.
► Distinct NMDA receptor subunits mediate the age-dependent effects of leptin.
► The age-dependent effects of leptin involve divergent signalling pathways.