|Figure 1. Ethanol toxicity in a developing rat brain model. Ethanol was administered to rats by several dosing regimens. The total dose ranged from 0 to 5 g/kg sc and was administered either in a single injection or in multiple injections spaced 2 hours apart. (A) Blood ethanol curves associated with each of several dosing regimens, descripbed in (B). (B) Severity of apoptotic neurodegeneration associated with each dose-blood ethanol curve. Adapted (with permission) from Ikonomidou, C. et al. (2000) Science 287:1056.|
Fetal alcohol syndrome is a neurotoxic syndrome resulting from exposure of a fetus to high levels of alcohol during pregnancy. Affected individuals display a range of behavioral disturbances including learning disabilities, hyperactivity, depression, and psychosis.1,2 The mechanisms through which ethanol exerts its deleterious effects are unknown, however. It is thought that the brain is particularly sensitive to ethanol during the brain growth spurt period, known as synaptogenesis, which occurs in humans during the last trimester of gestation. Recent studies in a rat model system help elucidate the mechanism of ethanol toxicity.3,4
During development of the central nervous system, a large number of different types of neuronal cells must make proper connections with other cells according to a precisely organized developmental program.5 Apoptosis is a normal part of this developmental program. Signals that promote or inhibit apoptosis of neuronal cells play a crucial role in establishing proper neuronal connections.
Ethanol is a known antagonist of NMDA glutamate receptors.6 A recent study demonstrated that blockade of these receptors results in widespread apoptotic neurodegeneration in infant rat brain.3 Subsequent studies examined the effect of ethanol on developing rat brain during the synaptogenic period (i.e., between embryonic day 19 and postnatal day 14).4 The percentage of apoptotic cells in 15 different brain regions was examined in rats on postnatal day 8.4 Apoptotic frequencies in untreated animals ranged from 0.13 to 1.55 per cent. The apoptotic frequency in brain regions of ethanol treated animals, however, increased by 1-2 orders of magnitude. Elevated levels of apoptosis were triggered only if the level of blood alcohol was maintained above a toxic threshold range of approximately 0.2% (200 mg/dL) for a minimum of 4 consecutive hours (see Figure 1).
Triggering of apoptosis by ethanol occurred during a distinct time window corresponding to the period of synaptogenesis. Different neuronal populations displayed transient sensitivity at different times. Histological sections revealed that the pattern of apoptosis induced by ethanol overlapped with, but was more extensive than that induced by NMDA antagonists. Therefore, agents that act on a variety of receptor types were examined for their apoptotic effects. No appreciable apoptosis was triggered by agents that block voltage-gated ion channels, kainic acid or muscarinic cholinergic receptors, or that act as agonists or antagonists of dopamine receptors. A strong apoptotic response was triggered by agents that activate GABAA receptors. Superimposing the apoptotic pattern elicited by NMDA antagonists with that of GABAergic agents gave a composite pattern closely resembling that induced by ethanol. In all cases, the apoptotic sensitivity coincided with synaptogenesis.
Transient ethanol exposure during synaptogenesis can delete millions of neurons from the developing brain. Different neuronal populations can be affected depending on the timing of the exposure. Therefore, ethanol toxicity can contribute to a wide variety of neurobehavioral disturbances.