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Figure 1 Ethanol-induced apoptotic neurodegeneration in the C57BL/6 mouse brain. (A) Photomicrograph of a silver-stained brain section from an 8-day-old mouse 24 hr after saline treatment. In this normal control brain, as in any normal brain during development, a few neurons in scattered distribution are undergoing degeneration. However, because the concentration of degenerating neurons in any given region is so low, the degenerating profiles are barely visible at this low magnification. (B) Photomicrograph of a silver-stained brain section from an 8-day-old mouse 24 hr after ethanol administration. Degenerating neurons (small black dots) are so abundant that they make various brain regions containing a high density of vulnerable neurons stand out in relief. Regions that are heavily affected at this brain level include the caudate nucleus, globus pallidus, hippocampus, hypothalamus, cingulate and parietal cortices, and various anterior thalamic nuclei. [From Olney, J. W., et al. (2000). Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis 5, 515-521.]

Figure 1 Ethanol-induced apoptotic neurodegeneration in the C57BL/6 mouse brain. (A) Photomicrograph of a silver-stained brain section from an 8-day-old mouse 24 hr after saline treatment. In this normal control brain, as in any normal brain during development, a few neurons in scattered distribution are undergoing degeneration. However, because the concentration of degenerating neurons in any given region is so low, the degenerating profiles are barely visible at this low magnification. (B) Photomicrograph of a silver-stained brain section from an 8-day-old mouse 24 hr after ethanol administration. Degenerating neurons (small black dots) are so abundant that they make various brain regions containing a high density of vulnerable neurons stand out in relief. Regions that are heavily affected at this brain level include the caudate nucleus, globus pallidus, hippocampus, hypothalamus, cingulate and parietal cortices, and various anterior thalamic nuclei. [From Olney, J. W., et al. (2000). Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis 5, 515-521.]

In a recent neuroimaging study of the brains of living FAE/FAS subjects, there was evidence for a generalized reduction in brain mass, especially in the thalamus and basal ganglia, but no sign of a gross or conspicuous defect in any given brain region. It was concluded that the deleterious effects of ethanol on the developing brain must occur by a mechanism that reduces brain mass at a cellular or molecular level in an evenly distributed manner. The findings of Ikonomi-dou et al. in infant rodents treated with ethanol fit this description very well. The pattern of neuronal deletion was very diffuse but with the most dense degeneration occurring in specific structures such as the thalamus and basal ganglia.

Ikonomidou et al. demonstrated that the cell death process induced by ethanol is an apoptotic process in which the developing neurons commit suicide. They concluded that ethanol drives neurons to commit suicide by a dual mechanism—blockade of NMDA receptors and excessive activation of GABAA receptors. They determined that the time window of vulnerability to this brain damage mechanism coincides with the brain growth spurt period. The brain growth spurt period is a period when synaptogenesis is occurring at a rapid rate, and neurons are expanding their dendritic arbors extensively to provide additional surface area for receiving newly formed synaptic connections. During this period neurons depend on a balanced level of excitatory and inhibitory input through NMDA glutamate and GABAA receptors, respectively. Either blockade of NMDA receptors or hyperactivation of GABAA receptors abnormally suppresses neuronal activity. By mechanisms that remain to be deciphered, suppressed activity during synaptogenesis translates into a message for the neuron to commit suicide. The role of the NMDA and GABAA receptor systems in this neurodegenera-tive syndrome was established by treating infant rodents with various agents that block NMDA receptors or agents that promote GABAa neurotransmission and showing that all such agents trigger massive apoptotic neurodegeneration during synapto-genesis. Treating infant rodents with agents that interact as either agonists or antagonists of other transmitter receptor systems did not elicit a neurode-generative response.

An important feature of these new findings is that only a transient exposure to ethanol—a single episode of ethanol intoxication—was required to trigger extensive apoptotic neurodegeneration. In terms of blood ethanol concentrations, it required elevations in the range of 180 mg/dl, lasting for approximately 2-4 hr, to produce a robust neurodegenerative response. If blood ethanol concentrations remained at this elevated level for longer than 4 hr, the severity of degeneration escalated rapidly. Extrapolating to the human situation, it seems unlikely that maternal ingestion of a single glass of wine with dinner during the third trimester would cause neurons to degenerate in the fetal brain, but if on a single occasion several alcoholic beverages are imbibed within a period of a few hours, this might approach or exceed the threshold for causing neurons in the fetal brain to commit suicide. A major problem in assessing risk is that there is no way to know precisely how to extrapolate from rodents to humans, but prudence dictates that the extrapolation be made conservatively because of unknown variables that might cause the human fetus to be substantially more sensitive than the rodent fetus to this brain damage mechanism.

Another important point is that within the brain growth spurt period different neuronal populations were found to have different temporal patterns for responding to the apoptosis-inducing effects of etha-nol. Thus, depending on the timing of exposure, different combinations of neuronal groups were deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this observation are recent findings by Famy and colleagues pertaining to FAE/FAS subjects who were studied in adulthood. In addition to a history of childhood hyperactivity/attention deficit disorder and varying degrees of learning impairment, a high percentage of these individuals were found to have adult-onset neuropsychiatric disturbances, including a 44% incidence of major depressive disorder and 40% incidence of psychosis. This is an important study that used a longitudinal research design to assess for the first time the full range of neuropsychiatric disturbances that human fetal exposure to ethanol can cause. Because ethanol effects on the fetus were not even suspected until 27 years ago, a prospective longitudinal study could not be completed until a cohort of individuals bearing the FAE/FAS diagnosis had grown to adulthood and begun manifesting adult-onset disturbances.

It is interesting to consider how mechanisms by which ethanol damages the immature brain compare with mechanisms by which ethanol might be damaging to the adult brain. The first important consideration is that ethanol has NMDA antagonist properties and it is known that NMDA antagonist drugs typically cause a specific type of neurodegenerative reaction in the adult brain to which the immature brain is not sensitive. The adult neurodegenerative reaction occurs by an excito-toxic mechanism and is detectable in the neuronal cytoplasm as a vacuolization reaction within 2-4 hr after drug treatment, and it has been shown that immature animals are totally insensitive to this neuro-toxic mechanism. However, if immature animals during the synaptogenesis period are treated with an NMDA antagonist drug, it causes a different type of neurodegenerative response—a response that is apo-ptotic rather than excitotoxic and causes neurodegeneration that becomes detectable at 16-24 hr and distributes in a pattern different from the adult pattern of degeneration. Thus, it is clear that drugs with NMDA antagonist properties have two different mechanisms by which they are damaging to the brain; one mechanism is operative only during a certain period in development, whereas the other is operative only in adulthood.

Given that ethanol has NMDA antagonist properties, it would be expected to cause one type of degeneration in the immature brain and another type of degeneration in the adult brain. However, empirical findings in animal studies indicate that ethanol produces a robust neurodegenerative reaction in the immature brain but does not, even at very high doses given acutely, produce the expected neurodegenerative reaction in the adult brain. To understand this paradox, it is necessary to analyze another major property of ethanol—its GABAmimetic property. During the period of synaptogenesis, GABAmimetic drugs are very toxic to the developing brain. They trigger massive apoptotic neurodegeneration in many regions of the developing brain. However, GABAmimetic drugs are not toxic to the adult brain. Instead, they are neuroprotective. They do not produce any neurotoxic effects when administered by themselves; when administered together with an NMDA antagonist drug, they protect against the mechanism by which NMDA antagonists damage the adult brain. Since ethanol has both NMDA antagonist and GABAmi-metic properties, the logical conclusion, based on all available evidence, is that the NMDA antagonist and GABAmimetic properties of ethanol act in concert to produce a "double-whammy" type of damage in the developing brain, whereas in the adult brain these two properties are subtractive—one property is neurotoxic and the other is neuroprotective—with the end result being that the neurotoxic potential is there but is not expressed, except perhaps under conditions of heavy chronic ethanol abuse.

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