Zinc/CaMK II Associated-Mitophagy Signaling Contributed to Hippocampal Mossy Fiber Sprouting and Cognitive Deficits Following Neonatal Seizures and Its Regulation by Chronic Leptin Treatment.

Li-Li Li,Mei-Fang Jin,Hong Ni

doi:10.3389/fneur.2018.00802

Abstract

The role of leptin in the pathogenesis of epilepsy is getting more and more attention in clinical and basic research. Although there are data indicating neuroprotective effects of elevated serum/brain leptin levels following acute seizures, no study to date has dealt with the impact of chronic leptin treatment on long-term brain injury following developmental seizures. The aim of this study was to evaluate whether chronic leptin treatment may have neuroprotective effects on cognitive and hippocampal mossy fiber sprouting following flurothyl-induced recurrent neonatal seizures and whether these effects are mediated by the zinc/CaMKII-associated mitophagy signaling pathway. Forty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned into two groups: neonatal seizure group and control group. At P13, they were further divided into control group, seizure group (RS), control + leptin (leptin, i.p., 2 mg/kg/day for 10 days), seizure+leptin group (RS+Leptin, 2mg/kg/day, i.p., for 10 consecutive days). Morris water maze test was performed during P27-P32. Subsequently, Timm staining and Western blotting were used to detect the mossy fiber sprouting and protein levels in hippocampus. Flurothyl-induced seizures (RS group) significantly down-regulated mitophagy markers PINK, Drp1, PHB, and memory marker CaMK II alpha while up-regulating zinc transporters ZnT3, ZnT4, ZIP7, and autophagy execution molecular cathepsin-E, which were paralleled with hippocampal aberrant mossy fiber sprouting and cognitive dysfunction. However, these changes were restored by chronic leptin treatment (RS+Leptin group). The results showed that leptin had neuroprotective effect on hippocampal pathological damage and cognitive deficits induced by neonatal seizures and suggested that Zinc/CaMK II associated-mitophagy signaling pathway in hippocampus may be a new target of leptin's neuroprotection, with potential value of translational medicine.

Highlights

Leptin, cloned in 1994 from white adipocytes, functions initially as an ob gene to reduce obesity by controlling appetitive behaviors via hypothalamic neurons [1]
The results showed that leptin treatment can prevent long-term decline in seizure threshold caused by neonatal seizures and the abnormal expression of hippocampal mossy fiber sprouting-related ZnT3/CB-D28k [18]
It was found that continuous (10 days) leptin treatment counteracted the long-term increased sprouting of hippocampal mossy fibers and cognitive impairment, as well as corrected the abnormal expressions of related gene in the hippocampus, including mitochondria markers PHB, PINK1, DRP1, and its executive molecular Cathepsin E, zinc transporter 3,4 (ZnT3, ZnT4), ZIP7 and memory marker CaMK II α. These findings suggest that zinc/CaMK II-associated mitophagy signaling may be involved in the long-term neurobehavioral and neuropathological changes caused by neonatal seizures, providing new clues to translational medicine in search of potential targets for epileptogenesis

Summary

Introduction

Leptin, cloned in 1994 from white adipocytes, functions initially as an ob gene to reduce obesity by controlling appetitive behaviors via hypothalamic neurons [1]. Leptin receptors have widely been discovered in diverse brain regions, especially hippocampus, which plays a role in hippocampal-dependent neuronal morphology, synaptic plasticity, and cognition [2, 3]. Patients with leptin deficiency due to mutations in the ob gene showed structural and functional changes in the brain, including the hippocampus, and replacement therapy with leptin corrects for these changes [4]. Leptin inhibits epileptiform-like activity in hippocampal neurons [6] and suppresses seizures in two rodent seizure models [7, 8]. Leptin deficient ob/ob mice exhibited an increased severity of pentylenetetrazol-induced seizures [9]. The neuroprotective effect of leptin in the status epilepticus induced by kainic acid or pilocarpine was reported [10, 11]

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