SAT-595 Early Weight Gain Impact onto the Arcuate Leptin Receptor Expressing Neurons Activity During Development

Abstract The arcuate nucleus (ARH) is considered the main mediator of the effects of leptin on energy homeostasis, as well, part of the hypothalamic circuitry through which the sex steroids mediate the ovulatory cycle and therefore reproduction. While it is known that aging influences synaptic plasticity of ARH neurons, the effects of increased weight gain early in life onto in the activity of ARH neurons are still poorly understood. In order to demonstrate whether prepubertal adiposity gain is able to modulate the synaptic transmission in leptin receptor (LepR)-expressing cells of the ARH, we employed a postnatal over-nutrition model by raising mice in small litters (SL), while control mice were maintained in regular litters (6-8 pups per litter). The spontaneous currents of LepR-expressing neurons in the ARH were measured by whole-cell patch-clamp recordings in hypothalamic slices obtained from prepubertal, pubertal and adult female LepR-reporter mice. As expected, mice raised in SL exhibited increased body weight compared to control mice at prepubertal and pubertal stage (prepubertal, t(59) = 6.9, P < 0.001; pubertal, t(59) = 5.3, P < 0.001), despite no difference at adult age (t(59) = 1.5, P = 0.4). By evaluating ARH neuronal activity we observed an increased average of excitatory and inhibitory currents frequency during development, in both control females (sEPSC: F(2, 46)= 17.76, P< 0.0001, sIPSC: F(2, 21)= 4.064, P= 0.0322) and in mice raised in SL (sEPSC: F(2, 49)= 27.76, P< 0.0001, sIPSC: F(2, 19)= 6.714, P= 0.0062). However, SL and control mice exhibited similar sEPSC amplitudes at all stages of development. A significant interaction between litter size and excitatory transmission frequency onto LepR-expressing cells were noted at the pubertal and adult stages (F(2, 95)= 3.164, P= 0.046), despite no changes in the amplitudes of these signals (interaction: F(2, 95) = 0.1516, P= 0.8596; age: F(2, 95) = 0.9961, P= 0.3731; litter size: F(1, 95) = 0.076, P= 0.7832). By evaluating the inhibitory transmission to ARH LepR-expressing neurons, no significant interaction between litter size and inhibitory transmission frequency were observed (F(2, 40) = 0.09271, P= 0.9117). However, the average sIPSC amplitude were significantly reduced in the ARH cells recorded from mice raised in SL, when compared to the control group (F(2, 42) = 22.86, P< 0.0001), despite no identifiable interaction between litter size and inhibitory transmission (F(2, 42) = 0.6619, P= 0.5212). Taken together our results suggest that early weight gain influences the excitatory transmission pattern in LepR-expressing neurons by increasing presynaptic excitatory inputs and suppressing postsynaptically transmission to ARH neurons.