New Insights and New Issues in Developmental Neurotoxicology

doi:10.1016/S0161-813X(01)00092-4

NeuroToxicology

Volume 23, Issue 6, December 2002, Pages 659-668

https://doi.org/10.1016/S0161-813X(01)00092-4 Get rights and content

Abstract

Here, I will review accumulating evidence that during the developmental period of synaptogenesis, also known as the brain growth spurt period, neurons are very sensitive to specific disturbances in their synaptic environment. During this period, abnormal increases in NMDA glutamate (Glu) receptor activity triggers excitotoxic neurodegeneration, and abnormal inhibition of neuronal activity (by blockade of NMDA Glu receptors or excessive activation of GABA_A receptors) triggers neuronal suicide (apoptosis). Only a transient disturbance, lasting for a few hours, is sufficient to trigger either excitotoxic or apoptotic neurodegeneration during this developmental period. Ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers widespread apoptotic neurodegeneration in the developing rat, mouse or guinea pig brain, and this provides a likely explanation for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The brain growth spurt 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 6th month of gestation to several years after birth. Thus, there is a period in fetal and neonatal human development, lasting for several years, during which immature central nervous system (CNS) neurons are exquisitely sensitive to environmental agents (the specific number and variety of which remains to be established) that can trigger widespread neurodegeneration by inducing specific abnormal changes in the synaptic environment. Agents identified thus far include drugs that may be abused by pregnant mothers (ethanol, phencyclidine (PCP) (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines) and many medicinals used in obstetric and pediatric medicine as sedatives, anti-convulsants or anesthetics (all general anesthetics are either NMDA antagonists or GABAmimetics). Many other chemicals in the human environment remain to be evaluated for their ability to cause developing CNS neurons to commit suicide, and this provides an exciting challenge for the field of developmental neurotoxicology.

Section snippets

INTRODUCTION

A wide variety of neuropsychiatric disturbances, ranging from mental retardation to schizophrenia, are believed to be the result of a combination of genetic and environmental influences, the latter impinging on the immature brain during critical stages of development. We have been exploring mechanisms by which environmental factors can disrupt development of the brain, thereby giving rise to neurobehavioral disturbances that may be expressed either in childhood or with delayed onset in

CONCLUDING REMARKS

Here, I have summarized recent findings pertaining to several environmental agents (ethanol, PCP, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, propofol, phenytoin, valproate) that have the potential to delete large numbers of neurons from the developing brain by a newly discovered mechanism involving interference in the action of neurotransmitters (Glu and GABA) at NMDA and GABA_A receptors during the synaptogenesis period, also known as the brain growth spurt

Acknowledgements

Supported by NIH Grants AG 11355, DA 05072, HD 37100, EY 08089, and a NARSAD Toulmin Distinguished Investigator Award.

References (68)

S.K Clarren et al.
Brain malformations related to prenatal exposure to ethanol
J. Pediatr.
(1978)
T.D Corso et al.
Multifocal brain damage induced by phencyclidine is augmented by pilocarpine
Brain Res.
(1997)
K Dikranian et al.
Apoptosis in the in vivo mammalian forebrain
Neurobiol. Dis.
(2001)
N.B Farber et al.
Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia
Biol. Psychiatr.
(1995)
B Grasl-Kraupp et al.
In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note
Hepatology
(1995)
B.J Gwag et al.
Slowly triggered excitotoxicity occurs by necrosis in cortical cultures
Neuroscience
(1997)
M Ishimaru et al.
Halothane prevents MK801 neurotoxicity in the rat cingulate cortex
Neurosci. Lett.
(1995)
M Lesort et al.
NMDA induces apoptosis and necrosis in neuronal cultures. increased APP immunoreactivity is linked to apoptotic cells
Neurosci. Lett.
(1997)
J.W Olney
Excitatory amino acids and neuropsychiatric disorders
Biol. Psychiatr.
(1989)
J.W Olney et al.
Kainic acid: a powerful neurotoxic analogue of glutamate
Brain Res.
(1974)

A.H Wyllie et al.

Cell death: the significance of apoptosis

Int. Rev. Cytol.

(1980)

M Ankarkona et al.

Lamin and β-tubulin fragmentation precedes chromatin degradation in glutamate-induced neuronal apoptosis

Neuroreport

(1996)

H.M Barr et al.

Identifying maternal self-reported alcohol use associated with fetal alcohol spectrum disorders

Alcohol Clin. Exp. Res.

(2001)

P Bittigau et al.

Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain

Ann. Neurol.

(1999)

P Bittigau et al.

Barbiturates and benzodiazepines cause apoptotic neurodegeneration in the developing rat brain

Soc. Neurosci. Abstr.

(1999)

P Bittigau et al.

Anti-epileptics which enhance GABAergic inhibition cause neuronal apoptosis in the developing CNS

Soc. Neurosci. Abstr.

(2000)

E Bonfoco et al.

Apoptosis and necrosis: two distinct events induced, respectively by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures

Proc. Natl. Acad. Sci. U.S.A.

(1995)

C Charriaut-Marlangue et al.

A cautionary note on the use of the TUNEL stain to determine apoptosis

Neuroreport

(1995)

D.W Choi

Excitotoxic cell death

J. Neurobiol.

(1992)

R.J Collins et al.

Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis

Int. J. Radiat. Biol.

(1992)

A.B Dessens et al.

Association of prenatal phenobarbital and phenytoin exposure with small head size and with learning problems

Acta Paediatr.

(2000)

K Dikranian et al.

Histological characterization of apoptotic neurodegeneration induced in the developing rodent brain by barbiturates and benzodiazepines

Soc. Neurosci. Abstr.

(1999)

J Dobbing et al.

The brain growth spurt in various mammalian species

Early Human Dev.

(1979)

C Famy et al.

Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects

Am. J. Psych.

(1998)

N.B Farber et al.

Action of ethanol at GABA_A receptors blocks neurotoxicity in the adult brain, but augments neurotoxicity in the developing brain

Soc. Neurosci. Abstr.

(1999)

I Ferrer et al.

Both apoptosis and necrosis occur following intrastriatal administration of excitotoxins

Acta Neuropathol.

(1995)

R.K Filipkowski et al.

DNA fragmentation in rat brain after intraperitoneal administration of kainate

Neuroreport

(1994)

A.S Fix et al.

Pathomorphologic effects of N-methyl-d-aspartate antagonists in the rat posterior cingulate/retrosplenial cerebral cortex

Drug Dev. Res.

(1994)

R.A Harris et al.

Ethanol increases GABA_A responses in cells stably transfected with receptor subunits

Alcohol Clin. Exp. Res.

(1995)

R.E Hartman et al.

Neonatal exposure to common anesthetics leads to spatial learning deficits in juvenile rats

Soc. Neurosci. Abstr.

(2001)

P.L Hoffman et al.

N-Methyl-d-aspartate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production

J. Neurochem.

(1989)

C Ikonomidou et al.

Hypobaric-ischemic conditions produce glutamate-like cytopathology in infant rat brain

J. Neurosci.

(1989)

C Ikonomidou et al.

Prevention of trauma-induced neurodegeneration in infant rat brain

Pediatr. Res.

(1996)

C Ikonomidou et al.

Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain

Science

(1999)

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Alterations of white matter integrity and subsequent white matter structural deficits are consistent findings in Fetal Alcohol Syndrome (FAS), but knowledge regarding the molecular mechanisms underlying these abnormalities is incomplete. Experimental rodent models of FAS have shown dysregulation of cytokine expression leading to apoptosis of oligodendrocyte precursor cells (OPCs) and altered oligodendrocyte (OL) differentiation, but whether this is representative of human FAS pathogenesis has not been determined.
Fetal brain tissue (12.2–21.4 weeks gestation) from subjects undergoing elective termination of pregnancy was collected according to an IRB-approved protocol. Ethanol (EtOH) exposure status was classified based on a detailed face-to-face questionnaire adapted from the National Institute on Alcohol Abuse and Alcoholism Prenatal Alcohol and Sudden Infant Death Syndrome and Stillbirth (PASS) study. Twenty EtOH-exposed fetuses were compared with 20 gestational age matched controls. Cytokine and OPC marker mRNA expression was quantified by Real-Time Polymerase chain reaction (qRT-PCR). Patterns of protein expression of OPC markers and active Capase-3 were studied by Fluorescence Activated Cell Sorting (FACS).
EtOH exposure was associated with reduced markers of cell viability, OPC differentiation, and OL maturation, while early OL differentiation markers were unchanged or increased. Expression of mRNAs for proteins specific to more mature forms of OL lineage (platelet-derived growth factor α (PDGFRα) and myelin basic protein (MBP) was lower in the EtOH group than in controls. Expression of the multifunctional growth and differentiation-promoting growth factor IGF-1, which is essential for normal development, also was reduced. Reductions were not observed for markers of early stages of OL differentiation, including Nuclear transcription factor NK-2 homeobox locus 2 (Nkx2.2). Expression of mRNAs for the proinflammatory cytokine, tumor necrosis factor-α (TNFα), and several proinflammatory chemokines was higher in the EtOH group compared to controls, including: Growth regulated protein alpha/chemokine (C-X-C motif) ligand 1 (GRO-α/CXCL1), Interleukin 8/chemokine (C-X-C motif) ligand 8 (IL8/CXCL8), Chemokine (C-X-C motif) ligand 6/Granulocyte chemotactic protein 2 (CXCL16/GCP2), epithelial-derived neutrophil-activating protein 78/chemokine (C-X-C motif) ligand 5 (ENA-78/CXCL5), monocyte chemoattractant protein-1 (MCP-1). EtOH exposure also was associated with an increase in the proportion of cells expressing markers of early stage OPCs, such as A2B5 and NG2. Finally, apoptosis (measured by caspase-3 activation) was increased substantially in the EtOH group compared to controls.
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Millions of children are exposed to general anesthetics every year to undergo surgical operations and painful interventions worldwide. Research in animals has raised substantial concerns regarding the effects of anesthetic exposure on the developing brain and several epidemiological studies have addressed this important clinical concern. This chapter assesses available animal studies into the effects of commonly used anesthetics on brain structure and cognitive function and their relevance to clinical pediatric anesthesia practice as well as the current clinical evidence. Studies were identified using searches of medical databases, queries of recent review articles, and personal records. The number of laboratory studies into anesthetic neurotoxicity has increased dramatically in the past 10 years, demonstrating compelling evidence for both brain structural abnormalities as well as impaired long-term cognitive outcomes following prolonged exposure to anesthetics early in life. In humans, several epidemiological studies have associated anesthesia for surgery early in life with subsequent neurobehavioral abnormalities, while others, including the interim results of a randomized controlled trial as well as a recent ambi-directional study, have not found any effect of inhaled anesthetic exposure in infancy on subsequent cognition. However, the potentially most susceptible age as well as the phenomenon's underlying mechanisms are not well described. Accordingly, given the serious implications for public health, further research, both in animals and in humans, is urgently needed to better define human applicability of animal data and to devise potential mitigating strategies.
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Ketamine, an FDA-approved N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used for general pediatric anesthesia. Accumulating evidence has indicated that prolonged exposure to ketamine induces widespread apoptotic cell death in the developing brains of experimental animals. Although mitochondria are known to play a pivotal role in cell death, little is known about the alterations in mitochondrial ultrastructure that occur during ketamine-induced neurotoxicity. The objective of this pilot study was to utilize classic and contemporary methods in electron microscopy to study the impact of ketamine on the structure of mitochondria in the developing rat brain. While transmission electron microscopy (TEM) was employed to comprehensively study mitochondrial inner membrane topology, serial block-face scanning electron microscopy (SBF-SEM) was used as a complementary technique to compare the overall mitochondrial morphology from a representative treated and untreated neuron. In this study, postnatal day 7 (PND-7) Sprague-Dawley rats were treated with ketamine or saline (6 subcutaneous injections × 20 mg/kg or 10 ml/kg, respectively, at 2-h intervals with a 6-h withdrawal period after the last injection, n=6 each group). Samples from the frontal cortex were harvested and analyzed using TEM or SBF-SEM. While classic TEM revealed that repeated ketamine exposure induces significant mitochondrial swelling in neurons, the newer technique of SBF-SEM confirmed the mitochondrial swelling in three dimensions (3D) and showed that ketamine exposure may also induce mitochondrial fission, which was not observable in the two dimensions (2D) of TEM. Furthermore, 3D statistical analysis of these reconstructed mitochondria appeared to show that ketamine-treated mitochondria had significantly larger volumes per unit surface area than mitochondria from the untreated neuron. The ultrastructural mitochondrial alterations demonstrated here by TEM and SBF-SEM support ketamine’s proposed mechanism of neurotoxicity in the developing rat brain.
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Citation Excerpt :
In our study, this domain has also turned out to be a significant predictor of recovery among patients with a FEP. Overall, the cause of cognitive deficits in psychotic disorders is still not clear; several etiological hypotheses have been postulated, such as the glutamate hypothesis, where cognitive disorders can be a consequence of the neurotoxic activity (Olney, 2002; Stahl, 2004). Other views involve reduced brain-derived neurotrophic factor (BDNF) levels (Buckley et al., 2007; Durany et al., 2001; Ikeda et al., 2008) which has been linked to cognitive performance (Aas et al., 2013).
Recovery in psychotic disorders remains a major challenge across mental health. Identifying predictors of recovery in first psychotic episodes is a priority in order to increase knowledge on underlying mechanisms of the illness and to obtain objective severity markers at initial phases. In this study we gathered sociodemographic, clinical and cognitive data to explore predictive variables of recovery after three years follow-up in a sample of 399 patients with a first episode of psychosis (FEP).
This is a longitudinal study including patients with a FEP. A dichotomic variable of recovery was created according to symptomatic and functional outcome after 3 years follow-up. Significant variables in univariate analysis were entered into a binary logistic regression to obtain a multivariate prediction model of recovery.
The predictive model was statistically significant and classified an overall of 76% of patients correctly, specifically 86.7% of patients that would not recover and 55% of the patients that would recover. From all the variables that where significantly different between recovered and not recovered patients, only speed of processing, executive functions and premorbid adjustment were found to be significant predictors of recovery.
This study provides evidence that the degree of basal impairment in cognitive functions related to the Prefrontal Cortex and a worst premorbid adaptation predict in a significant way which patients are less likely to recover three years after a FEP.

View all citing articles on Scopus

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New Insights and New Issues in Developmental Neurotoxicology

Abstract

Section snippets

INTRODUCTION

CONCLUDING REMARKS

Acknowledgements

J. Pediatr.

Brain Res.

Neurobiol. Dis.

Biol. Psychiatr.

Hepatology

Neuroscience

Neurosci. Lett.

Neurosci. Lett.

Biol. Psychiatr.

Brain Res.

Int. Rev. Cytol.

Lamin and β-tubulin fragmentation precedes chromatin degradation in glutamate-induced neuronal apoptosis

Neuroreport

Identifying maternal self-reported alcohol use associated with fetal alcohol spectrum disorders

Alcohol Clin. Exp. Res.

Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain

Ann. Neurol.

Barbiturates and benzodiazepines cause apoptotic neurodegeneration in the developing rat brain

Soc. Neurosci. Abstr.

Anti-epileptics which enhance GABAergic inhibition cause neuronal apoptosis in the developing CNS

Soc. Neurosci. Abstr.

Apoptosis and necrosis: two distinct events induced, respectively by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures

Proc. Natl. Acad. Sci. U.S.A.

A cautionary note on the use of the TUNEL stain to determine apoptosis

Neuroreport

Excitotoxic cell death

J. Neurobiol.

Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis

Int. J. Radiat. Biol.

Association of prenatal phenobarbital and phenytoin exposure with small head size and with learning problems

Acta Paediatr.

Histological characterization of apoptotic neurodegeneration induced in the developing rodent brain by barbiturates and benzodiazepines

Soc. Neurosci. Abstr.

The brain growth spurt in various mammalian species

Early Human Dev.

Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects

Am. J. Psych.

Action of ethanol at GABAA receptors blocks neurotoxicity in the adult brain, but augments neurotoxicity in the developing brain

Soc. Neurosci. Abstr.

Both apoptosis and necrosis occur following intrastriatal administration of excitotoxins

Acta Neuropathol.

DNA fragmentation in rat brain after intraperitoneal administration of kainate

Neuroreport

Pathomorphologic effects of N-methyl-d-aspartate antagonists in the rat posterior cingulate/retrosplenial cerebral cortex

Drug Dev. Res.

Ethanol increases GABAA responses in cells stably transfected with receptor subunits

Alcohol Clin. Exp. Res.

Neonatal exposure to common anesthetics leads to spatial learning deficits in juvenile rats

Soc. Neurosci. Abstr.

N-Methyl-d-aspartate receptors and ethanol: Inhibition of calcium flux and cyclic GMP production

J. Neurochem.

Hypobaric-ischemic conditions produce glutamate-like cytopathology in infant rat brain

J. Neurosci.

Prevention of trauma-induced neurodegeneration in infant rat brain

Pediatr. Res.

Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain

Science

Action of ethanol at GABA_A receptors blocks neurotoxicity in the adult brain, but augments neurotoxicity in the developing brain

Ethanol increases GABA_A responses in cells stably transfected with receptor subunits