Abstract
Microglia can 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 (hM4Di)-based modulation of microglia reduces the amount of spontaneous recurrent seizures (SRS) and epilepsy-associated hallmarks in a TLE mouse model.
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. Mice were unilaterally injected with kainic acid in the hippocampus to obtain epileptic mice with SRSs. We assessed neuronal and microglial markers after a four-day regimen with the designer drug deschloroclozapine (DCZ, 1 mg/kg). Another cohort of mice was continuously electroencephalogram (EEG) monitored. Changes in the amount of SRS, compared to baseline, were investigated immediately after DCZ-based microglial Gi-DREADD modulation and during a three-week washout.
Immunohistochemistry shows significantly less CD68 in microglial cells in the CA3 (p = 0,0131) and dentate gyrus (p = 0,0184) and a trend towards less neuronal activation, measured by c-fos, after DCZ injections in epileptic CX3CR1CreERT2/+:R26LSL-Gi-DREADD/+ (n = 5) compared to CX3CR1CreERT2/+:R26+/+ mice (n = 4-6). Preliminary data show no difference in total seizure amount during and immediately 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/+ (n = 9) compared to CX3CR1CreERT2/+:R26+/+ mice (n = 5).
These preliminary results show effects of microglial hM4Di-DREADD modulation on neuronal activation and a trend towards long-term effects on the number of SRS in the intrahippocampal kainic acid mouse model.
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. Mice were unilaterally injected with kainic acid in the hippocampus to obtain epileptic mice with SRSs. We assessed neuronal and microglial markers after a four-day regimen with the designer drug deschloroclozapine (DCZ, 1 mg/kg). Another cohort of mice was continuously electroencephalogram (EEG) monitored. Changes in the amount of SRS, compared to baseline, were investigated immediately after DCZ-based microglial Gi-DREADD modulation and during a three-week washout.
Immunohistochemistry shows significantly less CD68 in microglial cells in the CA3 (p = 0,0131) and dentate gyrus (p = 0,0184) and a trend towards less neuronal activation, measured by c-fos, after DCZ injections in epileptic CX3CR1CreERT2/+:R26LSL-Gi-DREADD/+ (n = 5) compared to CX3CR1CreERT2/+:R26+/+ mice (n = 4-6). Preliminary data show no difference in total seizure amount during and immediately 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/+ (n = 9) compared to CX3CR1CreERT2/+:R26+/+ mice (n = 5).
These preliminary results show effects of microglial hM4Di-DREADD modulation on neuronal activation and a trend towards long-term effects on the number of SRS in the intrahippocampal kainic acid mouse model.
| Original language | English |
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| Publication status | Unpublished - 2024 |
| Event | EMBO workshop - Microglia in health and disease - Genova, Italy Duration: 21 May 2024 → 24 May 2024 |
Conference
| Conference | EMBO workshop - Microglia in health and disease |
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| Country/Territory | Italy |
| City | Genova |
| Period | 21/05/24 → 24/05/24 |