Excitotoxicity is an important mechanism involved in perinatal
brain injuries.
Glutamate is the major excitatory
neurotransmitter, and most neurons as well as many oligodendrocytes and astrocytes possess receptors for
glutamate. Perinatal insults such as
hypoxia-
ischemia,
stroke,
hypoglycemia,
kernicterus, and
trauma can disrupt synaptic function leading to accumulation of extracellular
glutamate and excessive stimulation of these receptors. The activities of certain
glutamate receptor/channel complexes are enhanced in the immature brain to promote activity-dependent plasticity. Excessive stimulation of
glutamate receptor/
ion channel complexes triggers
calcium flooding and a cascade of intracellular events that results in apoptosis and/or
necrosis. Recent research suggests that some of these intracellular pathways are sexually dimorphic. Age dependent expression of different
glutamate receptor subtypes with varying abilities to flux
calcium has been associated with special patterns of selective vulnerability at different gestational ages. For example, selective injury to the putamen, thalamus and cerebral cortex from near total
asphyxia in term infants may be related to excessive activation of neuronal
NMDA and
AMPA type
glutamate receptors, while brainstem injury may be related primarily to stimulation of neuronal
AMPA/
kainate receptors. In contrast,
periventricular leukomalacia in premature infants has been linked to expression of
AMPA/
kainate receptors on immature oligodendrocytes. Insight into the molecular pathways that mediate perinatal
brain injuries could lead to therapeutic interventions.