Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NR
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Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons Dong Liang 1,2 & Fei Fan 3 & Wei Ding 3 & Yuan Fang 3 & Lan Hu 1,2 & Bibo Lei 3 & Mingqiang Zhang 3 Received: 2 April 2020 / Accepted: 25 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Neuregulin 1 (NRG1)–induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1’s effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IHexposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons. Keywords Neonatal hypoxia . Seizure susceptibility . Parvalbumin interneurons . NRG1-ErbB4 signaling . Environmental enrichment
Introduction Dong Liang and Fei Fan contributed equally to this work. * Bibo Lei [email protected] * Mingqiang Zhang [email protected] 1
Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin 2nd Road, Shanghai, China
2
Department of emergency, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, 999 Xiwang Road, Jiading District, Shanghai 201801, People’s Republic of China
3
Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu 6
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