Elsevier

Biochemical Pharmacology

Volume 62, Issue 4, 15 August 2001, Pages 401-405
Biochemical Pharmacology

Commentary
Neurotransmitters and apoptosis in the developing brain1

https://doi.org/10.1016/S0006-2952(01)00696-7Get rights and content

Abstract

In the immature mammalian brain during a period of rapid growth (brain growth spurt/synaptogenesis period), neuronal apoptosis can be triggered by the transient blockade of glutamate N-methyl-d-aspartate (NMDA) receptors, or the excessive activation of γ-aminobutyric acid (GABAA) receptors. Apoptogenic agents include anesthetics (ketamine, nitrous oxide, isoflurane, propofol, halothane), anticonvulsants (benzodiazepines, barbiturates), and drugs of abuse (phencyclidine, ketamine, ethanol). In humans, the brain growth spurt period starts in the sixth month of pregnancy and extends to the third year after birth. Ethanol, which has both NMDA antagonist and GABAA agonist properties, is particularly effective in triggering widespread apoptotic neurodegeneration during this vulnerable period. Thus, maternal ingestion of ethanol during the third trimester of pregnancy can readily explain the dysmorphogenic changes in the fetal brain and consequent neurobehavioral disturbances that characterize the human fetal alcohol syndrome. In addition, there is basis for concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.

Introduction

Apoptosis, or programmed cell death, also referred to as physiological cell death, takes place during normal development of the central nervous system. It is characterized by a sequence of very distinctive morphological changes in the dying neuron (recently reviewed by Ishimaru et al.[1] and Dikranian et al.[2]). In addition to recent advances in deciphering the molecular steps of apoptotic cell death in various in vitro systems [3], it is incumbent upon neuroscientists to develop a better understanding of mechanisms that regulate physiological apoptosis in the in vivo developing brain, since disruption of this physiological process may result in neurodevelopmental disorders. It is known from work with knockout mice that blocking various steps in the apoptotic cascade may cause severe migrational defects that are incompatible with life [4], [5], [6]. In addition, knockout experiments involving deletion of antiapoptotic genes cause mice to display severe neurological deficits and, in many cases, to die in utero or during the neonatal period [7], [8]. It seems likely that for a full understanding of the many developmental neuropathology syndromes that occur in humans, it will be necessary to take into consideration both genetically determined disturbances and environmental factors that can influence the physiological cell death process. Consistent with this assumption, we have demonstrated recently that transient interference in the action of certain neurotransmitters during a critical stage in development, a stage in which trillions of synaptic connections are being formed, can trigger apoptotic degeneration of millions of neurons that otherwise would not have been deleted from the developing brain [9], [10]. Here we will review evidence pertaining to this newly discovered mechanism and will discuss its relevance to human neurodevelopmental syndromes.

Section snippets

Distinguishing apoptosis from other cell death processes

Wyllie and colleagues [8], [11] proposed that all cell death processes can be classified as either apoptosis or necrosis, and much confusion has arisen as other researchers have attempted to grapple with this “either/or” classification system. The confusion is particularly great among neurobiologists because excitotoxicity, a cell death process to which most if not all CNS neurons are vulnerable, does not fit the Wyllie et al. definition of either apoptosis or necrosis. One source of confusion

Induction by NMDA antagonists of apoptotic neurodegeneration in the developing brain

Glutamate, acting at NMDA receptors, has trophic functions in the developing brain. Glutamate promotes proliferation and migration of neuronal progenitors and influences synaptic plasticity [16], [17]. During the brain growth spurt period [18], NMDA receptors undergo a period of hypersensitivity that renders neurons bearing NMDA receptors exceedingly sensitive to excitotoxic degeneration [19], [20]. During that exact same developmental period, which in the rat extends from late fetal life to

Induction by GABAergic agents of apoptotic neurodegeneration in the developing brain

In an attempt to study other possible mechanisms that regulate neuronal survival during brain development, we examined whether interference in the action of several other neurotransmitter systems might trigger apoptotic neurodegeneration. We found no appreciable apoptotic response to dopamine receptor agonists or antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptor antagonists, muscarinic cholinergic receptor antagonists, or blockers of voltage dependent

Induction by ethanol of apoptotic neurodegeneration in the developing brain

Ethanol is, and has been for thousands of years, the most widely abused drug in the world. In the 1970s it was recognized that in utero ethanol exposure of the human fetus can result in a neurodevelopmental syndrome called fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) [23], [24]. FAS is characterized by craniofacial anomalies, microcephaly, and mental retardation. FAS constitutes the more severe form of impairment due to intrauterine exposure to ethanol, whereas less severe cases,

Neurotransmitters, apoptosis, and the developing human brain

Transient exposure of the mammalian brain to ethanol during the synaptogenesis period causes the death of millions of neurons. This finding provides a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human FAE/FAS, in that the human synaptogenesis/brain growth spurt period includes the last 3 months of gestation [18]. The blood ethanol levels required to trigger apoptotic neurodegeneration in the immature rat brain (200 mg/dL lasting 4 hr or

Conclusions

In recent pharmacological studies, we have shown that the blockade of NMDA glutamate receptors or excessive activation of GABAA receptors during synaptogenesis triggers widespread apoptotic neurodegeneration in the developing rodent brain. Our findings have clinical significance in that the brain growth spurt in humans extends from the sixth month of gestation to three years after birth, and during this period immature humans are sometimes exposed to drugs that block NMDA receptors and/or are

Acknowledgements

This work was supported by DFG Grant Ik2/2-1 and NIH Grants AG 11355, DA 05072, EY 08089, and HD 37100. J.W.O. is an NARSAD 2000 Toulmin Distinguished Investigator Awardee.

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    Abbreviations: GABAA, γ-aminobutyric acid; NMDA; N-methyl-d-aspartate; PCP; phencyclidine; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

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