RGS14 limits seizure-induced mitochondrial oxidative stress and pathology in hippocampus

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Regulator of G protein signaling 14 (RGS14) is a scaffolding protein enriched in hippocampal CA2 pyramidal cells (PCs).
• RGS14 normally suppresses excitatory signaling in CA2 PCs, which are resistant to neurological insults like temporal lobe epilepsy (TLE).
• The role of RGS14 in hippocampal pathology during TLE remains largely unexplored.

Purpose of the Study:

• To investigate the role of RGS14 in moderating seizure behavior and hippocampal pathology following seizure activity.
• To determine if RGS14 offers protection to CA2 PCs during pathological insults.

Main Methods:

• Kainic acid (KA)-induced status epilepticus (KA-SE) in wild-type (WT) and RGS14 knockout (RGS14 KO) mice.
• Proteomic analysis to identify protein expression changes.
• In vitro assessment of mitochondrial respiration.
• Measurement of oxidative stress markers (3-nitrotyrosine) and microgliosis.

Main Results:

• RGS14 KO mice exhibited accelerated seizure onset and mortality compared to WT mice after KA-SE.
• KA-SE upregulated RGS14 expression in CA2 and CA1 PCs.
• Loss of RGS14 impacted proteins related to mitochondrial function and increased oxidative stress.
• RGS14 KO mice showed no difference in CA2 PC neuronal injury but a lack of microgliosis in CA1 and CA2.

Conclusions:

• RGS14 plays a critical role in limiting seizure activity and associated pathology in the hippocampus.
• RGS14 is upregulated post-seizure to support mitochondrial function and prevent oxidative stress in CA2 PCs.
• RGS14 influences microglial activation in the hippocampus during seizure recovery.