GLP-1 facilitates cerebellar parallel fiber glutamate release through PKA cascade in vitro in mice

Abstract Glucagon-like peptide-1 (GLP-1) is mainly secreted by preglucagon (PPG) neurons, which play important roles in modulation of neuronal activity and synaptic transmission through its receptors. In this study, we here studied the effect of GLP-1 on parallel fiber-Purkinje cell (PF-PC) synaptic transmission in mouse cerebellar slices, by whole-cell patch-clamp recording technique and pharmacology methods. In the presence of GABAA receptor antagonist, bath application of GLP-1 (100 nM) enhanced PF-PC synaptic transmission, which expressed an increase in amplitude of evoked excitatory postsynaptic synaptic currents (eEPSCs) and a decrease in paired-pulse ratio (PPR). GLP-1 induced enhancement of eEPSCs was abolished by a selective GLP-1 receptor antagonist, Exendin 9–39, as well as by extracellular application of a specific protein kinase A (PKA) inhibitor, KT5720. However, inhibition of postsynaptic PKA which PKI containing internal solution, failed to block GLP-1 induced enhancement of eEPSCs. In the presence of a mixture of gabazine (20 µM) and TTX (1 µM), GLP-1 receptor significantly increased the frequency of miniature excitatory postsynaptic synaptic currents (mEPSCs), but without change the amplitude of mEPSCs. The GLP-1 induced increase in the frequency of mEPSCs was blocked by Exendin 9–39, as well as by inhibition of PKA with KT5720. The results indicate that activation of GLP-1 receptor enhances glutamate release at PF-PC synapse via PKA signaling pathway, resulting in an enhancement of PF-PC synaptic transmission in vitro in mice. The finding suggests that GLP-1 plays critical role in modulation of cerebellar function by regulating the excitatory synaptic transmission at PF-PC synapses in living animals.