The CXCL12/CXCR4 signaling is required for DPP4 regulation of spontaneous inhibitory postsynaptic currents (sIPSCs)
Abstract Background: Previous data suggested that dipeptidyl peptidase-IV (DPP4) involved in the occurrence of febrile seizure (FS), but its potential mechanism remains to be determined. Here, we investigated whether DPP4 regulated gamma-aminobutyric acid (GABA) mediated spontaneous inhibitory postsynaptic currents (sIPSCs) via the downstream C-X-C Motif Chemokine Ligand 12 (CXCL12)/ C-X-C chemokine receptor type 4 (CXCR4) signaling in cultured hippocampal neurons submitted to hyperthermia(39.5-40°C). Methods: Whole cell patch- clamp method was used to test sIPSC in vitro after DPP4 inhibition or CXCL12 administration. The level of CXCL12 and CXCR4 was tested using western blot analysis. The effect of CXCR4 antagonist AMD3100 (5 mg/ml, i.c.v) on seizures were tested using electroencephalogram (EEG) in a FS model. Results: We found that pharmacological DPP4 inhibitor sitagliptin (Sita,100μM) treatment or siRNA-mediated DPP4 knockdown enhanced the mean amplitude and frequency of sIPSCs in vitro. DPP4 knockdown with siRNA increased protein level of CXCL12 and CXCR4. Furthermore, CXCL12 (10 nM) treatment enhanced inhibitory transmission by increasing the mean frequency and amplitude of sIPSCs in vitro. AMD3100 administration decreased seizure severity by increasing hippocampal GABA content in vivo. Conclusions: Our data suggest that CXCL12/CXCR4 signaling is required for DPP4 regulation of sIPSCs, supporting that DPP4 played a key role in the pathogenesis of FS.