GABA signaling plays an important role in the regulation of neuronal activity in the mammalian brain. The hippocampus has a high density of receptors for metabolic hormones (Lathe, 2001) which may affect neuronal excitability. It has been shown that insulin influences GABA signaling in the hippocampus (Wan et al., 1997, Jin et al., 2011). Glucagon-like peptide-1 (GLP-1) is another metabolic hormone, secreted by intestinal L-cells, that affects brain function (During et al., 2003, Acuna-Goycolea and van den Pol, 2004). We have examined whether GLP-1 and its analog exendin-4 (Ex-4) can modulate GABA-evoked responses and neuronal excitability in CA3 pyramidal neurons of the rat hippocampus. We used the whole-cell patch-clamp technique in voltage-clamp or current-clamp mode to record GABA-activated currents or change in the membrane potential and action potential (AP) frequency in hippocampal slices from 16-20 days old Wistar rats. Administration of GLP-1 (10 pM-10 nM) or Ex-4 (10-100 nM) evoke tonic GABA-activated currents and increased the frequency of synaptic GABA-activated currents as compared to control. Values are means ± S.E.M., compared by ANOVA. In control conditions tonic currents were 3.3 ± 4.4 pA (n = 5) and were about ten times larger after application of 100 nM Ex-4 (33.8 ± 5.6 pA; n = 5; P < 0.001). The frequency of synaptic GABA-induced currents increased by 96 ± 35 % when neurons were exposed to 10 nM Ex-4 (n = 5; P < 0.05). AP firing frequency decreased and neuronal membrane potential hyperpolarized upon GLP-1 application. When GLP-1 has been washed away membrane potential depolarized back to the initial value (Fig. 1). Our results demonstrate that GLP-1 and Ex-4 enhance GABA signaling that leads to decreased neuronal excitability in rat hippocampal CA3 pyramidal neurons.