Microglia seem able to alter the excitatory/inhibitory balance in temporal lobe epilepsy (TLE). Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable cell-specific modulation. We aim to investigate whether Gi-DREADD-based modulation of microglia reduces the amount of spontaneous recurrent seizures (SRS) in a mouse model of TLE.CX3CR1CreERT2/CreERT2 mice were crossed with R26LSL-Gi-DREADD/LSL-Gi-DREADD mice to obtain CX3CR1CreERT2/+:R26LSL-Gi-DREADD/+ and CX3CR1CreERT2/+:R26+/+ mice, as controls. Tamoxifen was administered to induce Gi-DREADD expression in CX3CR1+ cells. Four weeks later, mice were unilaterally injected with kainic acid in the hippocampus and an electrode was implanted for electroencephalogram (EEG) monitoring. When SRS are stabilised, mice were continuously EEG monitored. Changes in the amount of SRS after microglial Gi-DREADD modulation, by administration of the designer drug deschloroclozapine (DCZ, 1 mg/kg), was investigated, compared to baseline and vehicle injection. The long-term effects of microglial Gi-DREADD-based modulation on the number of SRS were evaluated during a three-week washout period.Immunohistochemistry confirmed co-localization of Gi-DREADDs with microglia, but not neurons or astrocytes. Preliminary data shows no difference in total seizure amount between CX3CR1CreERT2/+:R26LSL-Gi-DREADD/+ (n = 9) and CX3CR1CreERT2/+:R26+/+ mice (n = 5) after DCZ injections. There is a trend toward a lower total seizure amount 10-12 days and 22-24 days after DCZ injections in CX3CR1CreERT2/+:R26LSL-Gi-DREADD/+ compared to CX3CR1CreERT2/+:R26+/+ mice. No differences in seizure coverage or average seizure duration were observed. These preliminary results show a trend towards long-term, but not immediate, effects of Gi-DREADD modulation of CX3CR1+ cells on the number of SRS in the intrahippocampal kainic acid mouse model.