Loss of leptin receptors on hypothalamic POMC neurons alters synaptic

32 Adaptive changes in hypothalamic neural circuitry occur in response to alterations in 33 nutritional status. This plasticity at hypothalamic synapses contributes to the control of food 34 intake and body weight. Here we show that genetic ablation of leptin receptor gene 35 expression in POMC neurons (POMC: Lepr GFP) induces alterations at synapses on 36 POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: 37 Lepr GFP mice have decreased frequency of spontaneous GABAergic, but not 38 glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course 39 of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in 40 POMC: Lepr GFP mice is significantly slower than that of sIPSCs in control animals. While 41 analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is 42 associated with an increased amplitude and slow decay of mIPSCs onto POMC neurons in 43 POMC: Lepr GFP mice. Moreover, POMC neurons receive greater total ionic flux per 44 GABAergic event in the absence of leptin receptor signaling. In addition, treatment with the 45 alpha 3 subunit-containing GABAA receptor modulator SB-205384 enhances GABAergic 46 transmission only onto POMC neurons in POMC: Lepr GFP mice. Single cell RT-PCR 47 analysis further supports the expression of the alpha 3 subunit of the GABAA receptor on 48 POMC neurons in POMC: Lepr GFP mice. Finally, the responses to the GABAA receptor 49 agonist isoguvacine of POMC neurons are significantly smaller in POMC: Lepr GFP than in 50 control animals. Therefore, our present work demonstrates that loss of leptin signaling in 51 POMC neurons induces synaptic alterations at POMC synapses that may play an essential 52 role in energy homeostasis. 53