Plppr5 gene inactivation causes a more severe neurological phenotype and abnormal mitochondrial homeostasis in a mouse model of juvenile seizure.

Mice with inactivation of the Plppr5 gene (Plppr5-/-) had aggravated hypoxic-ischemic damage and partially weakened neuroprotection of melatonin (a mitochondrial targeted antioxidant), suggesting that abnormal mitochondrial homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Plppr5 inactivation disturbs mitochondrial homeostasis, which may cause long-term adverse consequences on behavior and cognition. We studied the long-term effects of Plppr5 knockout (KO) in both wild-type (WT) and Plppr5-null mice using a combination of neurobehavior, cognition, and standard cellular glutamate-induced excitotoxicity techniques. The change in mitochondrial membrane potential was determined by detecting MitoTracker Green FM and MitoTracker Red CMXROS with a Gallios flow cytometer. Our results suggest that Plppr5 gene knockout aggravated the impairment of exploratory behavior (open field test) and memory (novel object recognition and passive avoidance tests) in Plppr5-null mice following juvenile seizures. Furthermore, Plppr5 gene silencing aggravated the decrease in the cell survival rate of HT22 cells treated with glutamate for 24 h and further resulted in a decrease in superoxide dismutase (SOD) levels and the ratio of active mitochondria and a parallel increase in the reactive oxygen species (ROS) content. Interestingly, silencing the Plppr5 gene alone in vitro is sufficient to reduce the cell survival rate, aggravate oxidative stress damage, reduce the proportion of surviving mitochondria, and upregulate mitophagy activity. In summary, the present data reveal the first direct link between Plppr5 KO and neurobehavioral and cognitive impairment following juvenile seizures and provide a potential mechanistic explanation for the adverse consequences. Given that silencing the Plppr5 gene is sufficient to upregulate mitophagy activity and aggravate oxidative stress neuronal damage, our results suggest that Plppr5 substrates and/or mitophagy-based treatments may provide valuable new targets for the treatment of developmental convulsive brain injury.