Mechanisms of neonatal seizures in a mouse model of term-equivalent cerebral hypoxia-ischemia

2015 Pilot Project Read More


Principal Investigator: Michael Wong (WashU Neurology)
Collaborator: Rafael Galindo (WashU Neurology)


Neonatal cerebral hypoxia-ischemia (HI) is a major cause of seizures in the newborn period as well as a very important cause of symptomatic infantile and childhood epilepsy later in life. However, the biological mechanisms that lead to neonatal seizures and subsequent development of epilepsy in this patient population remains poorly understood. Furthermore, reliable animal models to systematically study clinical and electrographic seizures during and after neonatal HI are lacking. Utilizing in vivo real-time neonatal electroencephalography (EEG) this pilot project first aims at developing a technique for the identification and characterization of rodent neonatal seizures during and after neonatal HI.  A second aim of this project is to better understand the biological mechanisms involved in acute and chronic seizure generation. Specifically, we will investigate whether depletion of SARM protein or overexpression of NMNAT proteins will decrease acute, subacute and chronic seizures following HI. Alteration in the metabolic homeostasis of ischemic immature neurons is known to adversely affect baseline neuronal activity, promote neuronal degeneration and affect early network organization resulting in overall decreases in seizure threshold thus increasing epilepsy risk. SARM and NMNAT are two proteins involved in the generation of NAD+, an essential molecule involved in energy metabolism. Studies by Rafael Galindo demonstrate that SARM depletion or NMNAT upregulation result in significant decreases in acute mouse pup mortality during brain hypoxia-ischemia, decrease neuronal cell death and total brain tissue injury in brain regions that are known to trigger seizures. Therefore, the above effects by SARM and NMNAT may decrease the risk for seizure generation and may help further elucidate the biological pathways involved in epileptogenesis associated with neonatal birth asphyxia.

Grants and Awards

“Neuroprotective Actions of hCG in a Mouse Model of Term and Preterm Brain Injury”
NIH/NINDS R01NS12234 (PI, Galindo; Co-investigator, Wong)
Public Health Statement: NARRATIVE Human chorionic gonadotropin (hCG) is a placentally derived hormone with beneficial properties against the effects of newborn cerebral injury. Using a mouse model of neonatal hypoxia- ischemia, this study proposes to explore the neurobiological mechanisms responsive for the anti- degenerative function of this hormone in the injured preterm and term brain. This study is projected to advance our understanding of hCG receptors in the immature brain with the ultimate intend to develop new treatment strategies for the devastating neurological consequences of birth asphyxia.

“Neurofunctional effects of NMNAT overexpression and SARM depletion in newborn hypoxia-ischemia”
McDonnell Center for Cellular and Molecular Neurobiology (PI, Galindo)

“A mouse model of infantile spasms in tuberous sclerosis”
NIH/NINDS R21 NS104522-01 (PI, Wong)
Public Health Relevance Statement: Infantile spasms (IS) is a developmental epilepsy syndrome of infancy due to a variety of genetic and acquired causes and is strongly associated with a poor long-term neurological prognosis, including intellectual disability, autism, and chronic epilepsy. Tuberous Sclerosis Complex (TSC) is a common genetic cause of IS and is often viewed as a model disease that has mechanistic and therapeutic relevance to other developmental brain disorders. The research in this grant aims to develop a novel animal model of IS in TSC, which should have important future clinical and translational applications for investigating mechanisms and identifying novel therapeutic targets for IS.


Rensing N, Johnson KJ, Foutz TJ, Friedman JL, Galindo R, Wong M. Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a moue model of tuberous sclerosis complex. Epilepsia 2020; 61:879-891.

Rensing, N, Moy, B, Friedman, JL., Galindo, R, Wong, M. Longitudinal analysis of developmental changes in electroencephalography patterns and sleep-wake states of the neonatal mousePLoS ONE, 13 (11), art. no. e0207031, (2018).

Updated April 2021


Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.

Michael Wong


This pilot project is made possible by the Danforth Foundation Challenge Endowment.

Danforth Challenge Endowment