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

2015 Pilot Project Read More

Investigators

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

Description

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.

Investigator

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

Michael Wong

Support

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

Danforth Challenge Endowment