Inhibition of DPP4 enhances inhibitory synaptic transmission through activating the GLP-1/GLP-1R signaling pathway in a rat model of febrile seizures

Dipeptidyl peptidase-IV (DPP4) is a cell surface serine peptidase widely expressed in the brain. Recent studies suggest that DPP4 contributes to the development of febrile seizures (FS); however, the underlying mechanism is still unclear. Thus, we investigated the role of DPP4 in the progression of FS at the molecular and electro-physiological levels using FS models in vivo and in vitro. Herein, we found that both the mRNA and protein levels of DPP4 were upregulated in the FS model. Administration of the pharmacological DPP4 inhibitor sitagliptin suppressed the hyperthermia-induced neuronal excitability as determined via whole-cell patch-clamp recordings in vitro. Interestingly, sitagliptin administration activated the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) pathway by increasing the expression of GLP-1 and GLP-1R in a rat model of FS. Moreover, administration of the GLP-1R inhibitor exendin9-39 increased seizure severity, and sitagliptin reversed the effect, as shown in the electroencephalogram (EEG) and patch-clamp results in a rat model of FS. Furthermore, the GLP-1R-mediated reduction in GABAergic transmission was enhanced by sitagliptin and DPP4 knockdown through increasing miniature inhibitory post-synaptic currents (mIPSCs) in vitro accompanied by increased synaptic release of GABA in vivo. Taken together, our results demonstrate a role of DPP4 in regulating GABAergic transmission via the GLP-1/GLP-1R pathway. These findings indicated that DPP4 may represent a novel therapeutic strategy and target for FS.