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Published on: May 16, 2019
Seizure progression triggered by IQSEC3 loss is mitigated by reducing activated microglia in mice
Dongseok Park1, Seungjoon Kim1, Hyeonho Kim1
1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Abstract:
IQSEC3, a guanine nucleotide exchange factor for ADP-ribosylation factors (ARF-GEFs) is specifically expressed at GABAergic synapses, and its loss increases seizure susceptibility in mice. However, the contribution of microglia to initiation and/or progression of seizures in IQSEC3-deficient mice has not been investigated. In the current study, we show that mice with hippocampal dentate gyrus (DG)-specific IQSEC3 knockdown (KD) exhibit microglial activation and death of DG granule cell. Furthermore, treatment of IQSEC3-KD mice with minocycline, an inhibitor of microglial activation, blocks DG granule neuron cell death and the occurrence of spontaneous seizures without affecting GABAergic synapse deficits or loss of somatostatin. Our results suggest that microglial activation is involved in a subset of IQSEC3-KD-induced epileptogenesis stages, and that its regulation could be an alternative strategy for managing epilepsy.
Insights
Loss of IQSEC3 (a guanine nucleotide exchange factor) leads to microglial activation and seizures. Inhibiting microglial activation prevents neuron death and seizures in IQSEC3-deficient mice, suggesting a new epilepsy management strategy.
Area of Science:
- Neuroscience
- Cell Biology
- Epilepsy Research
Background:
- IQSEC3, an ADP-ribosylation factor guanine nucleotide exchange factor (ARF-GEF), is crucial for GABAergic synapses.
- Loss of IQSEC3 in mice elevates seizure susceptibility, but the role of microglia remains unknown.
Purpose of the Study:
- To investigate the contribution of microglia to epileptogenesis in IQSEC3-deficient mice.
- To explore minocycline's effect on neuronal death and seizures in IQSEC3 knockdown models.
Main Methods:
- Hippocampal dentate gyrus (DG)-specific IQSEC3 knockdown (KD) in mice.
- Assessment of microglial activation, DG granule cell death, and spontaneous seizures.
- Treatment with minocycline, a microglial activation inhibitor.
Main Results:
- IQSEC3 KD mice showed microglial activation and DG granule neuron death.
- Minocycline treatment prevented neuron death and seizures in IQSEC3 KD mice.
- Minocycline did not affect GABAergic synapse deficits or somatostatin loss.
Conclusions:
- Microglial activation contributes to IQSEC3 KD-induced epileptogenesis.
- Inhibiting microglial activation may offer a novel therapeutic strategy for epilepsy management.
