title: Altered expression of KCC2 in GABAergic interneuron contributes prenatal stress-induced epileptic spasms in infant rat.
abstract: Long-term stress during pregnancy causes neurologic deficits to offspring with altered gamma-aminobutyric acid (GABA) system in the brain. However, it is not clear how prenatal stress affects the maturing GABAergic interneurons and the resulting abnormalities in infantile seizures. Here, we showed that prenatal stress alters the maturation of GABA inhibitory system using a seizure model induced by prenatal stress. Prenatal stress with betamethasone or acute immobilization stress (AIS) on gestational day 15 increased the seizure susceptibility to N-methyl-d-aspartate-triggered spasms on postnatal day 15. The expression of GABA was lower in the prenatally stressed group, which compromise the decrease of glutamate decarboxylase 67-immunopositive cells. Prenatal stress markedly decreased the expression of K(+)/Cl(-) co-transporter (KCC2) in the cortex. GABA induced membrane depolarization demonstrated prenatal stress models had significant higher membrane depolarization compared to control. GABA increased KCC2 expression in cultured cortex-containing slices. Taken together, our results showed that prenatal stress with betamethasone or AIS altered the maturation of GABAergic progenitors and resulted in the lack of GABA input, which in turn, decreased KCC2 expression and lowered seizure threshold. We conclude that delayed GABA excitatory/inhibitory shift would render the cortical neuronal circuit more susceptible to excitatory input in prenatal stress induced seizure.
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea; Department of Pediatrics, Chungnam National University Hospital, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Baek
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Yi
authors.affiliation: Department of Physiology, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Sudip
authors.initials: S
authors.lastname: Pandit
authors.affiliation: Department of Physiology, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea; Department of Pediatrics, Chungnam National University Hospital, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea.
authors.forename: Hyeok Hee
authors.initials: HH
authors.lastname: Kwon
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Enji
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea; Department of Plastic Surgery, Chungnam National University Hospital, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea.
authors.forename: Sena
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea; Anesthesia and Pain Medicine, Chungnam National University Hospital, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea.
authors.forename: Nara
authors.initials: N
authors.lastname: Shin
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Eunjee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 266, Jung-gu, Daejeon, 301-747, Republic of Korea. Electronic address: visnu528@cnu.ac.kr.
authors.forename: Dong Woon
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Chungnam National University Hospital, Brain Research Institute, Chungnam National University School of Medicine, Munwha-ro 282, Jung-gu, Daejeon, 301-721, Republic of Korea. Electronic address: childlove@cnu.ac.kr.
authors.forename: Joon Won
authors.initials: JW
authors.lastname: Kang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001623:Betamethasone / Q000633:toxicity; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D015870:Gene Expression; D005938:Glucocorticoids / Q000633:toxicity; D007103:Immobilization / Q000009:adverse effects / Q000523:psychology; D007395:Interneurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000378:metabolism*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics; D000096922:K Cl- Cotransporters
chemical_list: D001623:Betamethasone; D005938:Glucocorticoids; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: Epilepsy; Gamma-aminobutyric acid; Glutamate decarboxylase 67; K(+)/Cl(−) co-transporter; Prenatal stress; Seizure