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Background: Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia., Methodology/principal Findings: We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP), or saline, on postnatal day 2 (P2) or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7., Conclusions: These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathological and neurobehavioral consequences than a single treatment.

Administration of ethanol to rodents during the synaptogenesis period induces extensive apoptotic neurodegeneration in the developing brain. This neurotoxicity may explain the reduced brain mass and neurobehavioral disturbances in human Fetal Alcohol Syndrome (FAS). Here, we report binge-like exposure of infant mice to ethanol on a single postnatal day triggered apoptotic death of neurons from diencephalic structures that comprise an extended hippocampal circuit important for spatial learning and memory. The ethanol exposure paradigm yielding these neuronal losses caused profound impairments in spatial learning and memory at 1 month of age. This impairment was significantly attenuated during subsequent development, indicating recovery of function. Recovery was not associated with increased neurogenesis, suggesting plastic reorganization of neuronal networks compensated for early neuronal losses. We hypothesize that neuroapoptotic damage in homologous regions of human brain underlies cognitive deficits in FAS and the human brain of FAS victims has a similar capacity to effect functional recovery.

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre- and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABA(A) receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

Deals with a study which examined the relationship of early exposure to common anesthetic agent with apoptotic neurodegeneration in the developing rat brain. Materials and methods; Results; Discussion.

• Anesthetic/sedative agents delete cells in the developing brain by elevated apoptosis. • Developmental exposure to these agents may result in long-term functional impairments. • Well-designed animal models provide sensitivity for assessing behavioral deficits. Fifteen years ago Olney and colleagues began using animal models to evaluate the effects of anesthetic and sedative agents (ASAs) on neurodevelopment. The results from ongoing studies indicate that, under certain conditions, exposure to these drugs during development induces an acute elevated apoptotic neurodegenerative response in the brain and long-term functional impairments. These animal models have played a significant role in bringing attention to the possible adverse effects of exposing the developing brain to ASAs when few concerns had been raised previously in the medical community. The apoptotic degenerative response resulting from neonatal exposure to ASAs has been replicated in many studies in both rodents and non-human primates, suggesting that a similar effect may occur in humans. In both rodents and non-human primates, significantly increased levels of apoptotic degeneration are often associated with functional impairments later in life. However, behavioral deficits following developmental ASA exposure have not been consistently reported even when significantly elevated levels of apoptotic degeneration have been documented in animal models. In the present work, we review this literature and propose a rodent model for assessing potential functional deficits following neonatal ASA exposure with special reference to experimental design and procedural issues. Our intent is to improve test sensitivity and replicability for detecting subtle behavioral effects, and thus enhance the translational significance of ASA models. [ABSTRACT FROM AUTHOR]