Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus

Abstract

It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission.

Prolonged maternal separation induces undernutrition and systemic inflammation with disrupted hippocampal development in mice

“…Leptin has been recognized to be important for hippocampal synaptic function [53]. Noteworthy, leptin modulates GABAergic transmission in developing CA3 pyramidal cells of newborn rats [54], a field of the hippocampus where we found poor synaptophysin immunolabeling in PMS-challenged mice.…”

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions

“…Leptin also potentiates GABAergic transmission in postsynaptic CA3 pyramidal cells from the hippocampi of newborn rats (Guimond et al, 2014). The basal activity of these cells is reduced in leptin-deficient mice, as is a marker of presynaptic GABA synthesis, indicating that leptin signalling is critical for GABAergic transmission in the developing hippocampus (Guimond et al, 2014). In addition, chronic leptin treatment during the first two postnatal weeks alters the expression of genes involved in NMDA signalling and synaptic machinery and reduces long-term potentiation in pre-weaning rats (Walker et al, 2007).…”

“…In rodents, an important period of synaptogenesis and dendritic spine formation in the developing hippocampus coincides with the peak of the postnatal leptin surge in rodents, which is significant as leptin induces excitatory synaptogenesis and promotes dendritic spine formation in the adult hippocampus (Dhar et al, 2014a,b). Leptin also potentiates GABAergic transmission in postsynaptic CA3 pyramidal cells from the hippocampi of newborn rats (Guimond et al, 2014). The basal activity of these cells is reduced in leptin-deficient mice, as is a marker of presynaptic GABA synthesis, indicating that leptin signalling is critical for GABAergic transmission in the developing hippocampus (Guimond et al, 2014).…”

GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function

“…As current evidence suggests that leptin does not directly act on GnRH neurons through classic cascades associated with leptin receptor activation [95], it is possible that the enhanced GABAergic postsynaptic response to leptin following fasting still involves some change in the GABA A R population on these GnRH neurons. Indeed, in the immature system, leptin has been shown to potentiate GABAergic-PSCs through an increase in the expression of functional GABAergic synapses as well as an induction of multiple signaling molecules thought to be involved in synaptic plasticity [96]. Thus, the effects of fasting-stress on GnRH activity may involve both changes in presynaptic inhibitory drive and alterations in the GABA A R profile on GnRH neurons.…”