The hippocampus is an established center for memory and learning but it is less well known that it also governs body physiology. It is, therefore, not surprising that the hippocampus can sense physiological parameters and robustly expresses a number of receptors for a variety of molecules including metabolic hormones (1). We, nevertheless, know relatively little about how the metabolic hormones modulate hippocampal neuronal function. Do the hormones modulate the excitatory or the inhibitory system or both? Or, when there is too much or too little of these molecules e.g. insulin or glucagon-like peptide-1 (GLP-1), do these hormones then contribute to or even cause disease states, like decreased memory formation, increased seizure frequency or strength or even neuronal death like can occur in dementia, Alzheimer disease, epilepsy, diabetes and multiple sclerosis? We have studied the effects of insulin and GLP-1 on GABA-activated currents in rat hippocampal pyramidal neurons. The insulin receptor is prominently expressed in the hippocampus suggesting that insulin regulates hippocampal function (1). We have identified a molecular target of insulin signaling in the CA1 pyramidal neurons, the output neurons of the hippocampus (2). In acute hippocampal brain slices, physiological concentrations of insulin (1 nM) “turn-on” new, extrasynaptic GABA-A receptors in the CA1 pyramidal neurons. These channels are activated by more than a million times lower GABA concentration (EC50 17 + 4 pM) than the synaptic channels and generate tonic currents. The channels are inhibited by GABA-A receptors antagonists and have novel pharmacology as flumazenil and zolpidem are inverse agonists. The results are consistent with the channels containing at least α5βγ2 GABA-A receptor subunits. Activation of the channels results in decreased action potential firing. Importantly, our results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed. GLP-1, another metabolic hormone, is secreted by intestinal L cells. Application of GLP-1 (10 pM – 10 nM) or its analog exendin-4 (10 – 100 nM) evoked tonic currents and increased the frequency of synaptic GABA-activated currents as compared to control in the rat hippocampal CA3 pyramidal neurons. The neuronal membrane potential hyperpolarized upon GLP-1 application and the action potential frequency decreased. When GLP-1 was removed, the membrane potential depolarized back to the initial value and the action potential frequency recovered (n = 5). Our findings demonstrate an unexpected hormonal control of GABA-A receptor subtypes and excitability of hippocampal neurons. The results have implications for not only normal function but also diseases of the hippocampus.