Frances E Jensen — Page 2

PubMed2002

Relationship between encephalopathy and abnormal neuronal activity in the developing brain.

Infantile spasms represent a unique age-specific epileptic syndrome that is often associated with a focal or diffuse encephalopathy and can result in severe neurodevelopmental delay and retardation. The behavioral and electroencephalogram (EEG) phenotype of infantile spasms is similar, despite its association with multiple neurological disease states. The stereotypy suggests that the spasms originate from a highly age-specific hyperexcitable network. Treatment strategies for infantile spasms remain largely empirical due to the lack of understanding of the underlying neurochemistry and circuitry. This chapter reviews experimental evidence for the presence of unique developmental factors that appear to promote hyperexcitability in the immature brain and that may play a role in the generation of infantile spasms. In addition, this chapter evaluates the potential interplay between an associated developmental encephalopathy and enhanced neuronal hyperexcitability in infantile spasms.

Brain↗

PubMedDate not supplied

The role of glutamate receptor maturation in perinatal seizures and brain injury.

The perinatal age window is characterized by vulnerability to age-specific patterns of injury. Hypoxia/ischemia occurs in a number of settings both in term and preterm neonates, yet the patterns of response appear dependent upon the age of the infant. In the preterm neonate, hypoxic/ischemic insults result in selective white matter injury, termed periventricular leukomalacia (PVL), with little or no cortical pathology. However, in term babies, hypoxic encephalopathy is the most common cause of seizures, and also can result in cortical infarction. Extracellular glutamate accumulates in the setting of hypoxia/ischemia, and excess activation of glutamate receptors has been implicated in hypoxic/ischemic cellular death. Glutamate receptors are developmentally regulated in both neuronal and glial cells within the brain. Using rodent models, we have shown that hypoxia/ischemia results in selective white matter injury in postnatal day (P) seven rat pups, while hypoxia causes seizures in P10-12 rats, but not at younger or older ages. We have further demonstrated that antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor subtype block white matter injury at P7 and seizures at P10. We have shown that AMPA receptors are relatively overexpressed in oligodendrocytes (OLs) within white matter at P7 and in neurons in cortex and hippocampus at P10. Hence maturational patterns of glutamate receptor expression correlate with age-specific regional susceptibility to injury to hypoxia/ischemia. While glutamate receptor blockade represents a rational strategy in the treatment of perinatal hypoxic/ischemic brain injury, it is unclear what role variations in their expression play in normal development and plasticity. Further investigation of patterns of glutamate receptor subunit expression in human brain and in experimental animal models is necessary to determine potential age specific strategies as well as adverse effects.

Animals↗