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Exp Neurobiol. 2019 Aug 31;28(4):529-536. doi: 10.5607/en.2019.28.4.529.

Calpain-2 as a Treatment Target in Prenatal Stress-induced Epileptic Spasms in Infant Rats.

Kwon HH1,2,3, Neupane C1,4, Shin J1,2, Gwon DH1,2, Yin Y1,2, Shin N1,2, Shin HJ1,2,5, Hong J2,5, Park JB1,5,4, Yi Y3, Kim DW1,2,5, Kang JW1,5,3.

Author information

1
Department of Medical Science, Chungnam National University, Daejeon 35015, Korea.
2
Department of Anatomy, School of Medicine, Chungnam National University, Daejeon 35015, Korea.
3
Department of Pediatrics, Chungnam National University Hospital, Daejeon 35015, Korea.
4
Department of Physiology, School of Medicine, Chungnam National University, Daejeon 35015, Korea.
5
Brain Research Institute, School of Medicine, Chungnam National University, Daejeon 35015, Korea.

Abstract

Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K+/Cl- co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-Daspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed betamethasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.

KEYWORDS:

Calpain; Epilepsy; Glutamate decarboxylase 67; K+/Cl- co-transporter; KCC2; NMDA

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