Elsevier

Neuroscience

Volume 116, Issue 2, 31 January 2003, Pages 383-391
Neuroscience

Original contribution
Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats

https://doi.org/10.1016/S0306-4522(02)00716-9Get rights and content

Abstract

Premature and full-term human infants are at considerable risk of excitotoxic-mediated brain damage due to hypoxia–ischemia, infection or other trauma. Glutamate receptor activation is a major source of excitoxicity in the adult and developing brain, and the hippocampus is particularly vulnerable to damage. The seven-day-old rat is a widely used model of pediatric brain damage, in large part due to the relative insensitivity of the brain to exogenous glutamate treatment prior to this age. We have reexamined the possible role of glutamate in pediatric brain damage in the newborn rat using kainic acid treatment and attending to the sex of the animal as well as the effects of pretreatment with the gonadal steroid estradiol. Consistent with previous studies, we found no evidence of damage 7 days posttreatment in the CA1 region of the hippocampus in males or females. There was also little to no damage in the CA2/3 or dentate gyrus of males. In females, however, kainic-acid treatment induced substantial damage in the dentate gyrus and moderate damage in CA2/3, as assessed by neuron number and regional volume. Pretreatment with estradiol was protective against kainic acid-induced damage in females but was permissive for damage in the dentate gyrus of males. Estradiol treatment in the absence of kainic acid treatment was also neuroprotective in females in that it increased neuron number and volume throughout the hippocampal formation, suggesting that the basis of the sex difference observed in hippocampal volume was hormonally mediated. There was no effect of exogenous estradiol given to males in the absence of kainic acid. We conclude that the newborn female rat brain, but not the male, is sensitive to glutamate-mediated toxicity and that gonadal steroids play a complex role in both naturally occurring sex differences in hippocampal volume and response to injury.

Section snippets

Animals and treatment

Subjects were first-generation descendants of Sprague–Dawley albino rats from Charles River Laboratory (Wilmington, MA, USA). Female rats were bred in the University of Maryland School of Medicine animal colony. Pregnant females were checked daily for the presence of pups and day of birth was designated as PN0. Litters were excluded which did not contain at least four male and four female pups. All animals were housed under a 12-h light/dark cycle, with food and water provided. All animal

Brain/body mass

Analysis of potential systemic effects on pup growth and development by KA, estradiol and the combination of estradiol and KA was assessed via measurements of body and brain mass. There were no significant differences between groups in either measure (Table 2).

Neun-ir neuron counts

A sex difference in neuron number (Fig. 1) and mean volume is apparent throughout the hippocampal formation (Table 3). Comparisons of NeuN-ir neuron counts in the female versus male control demonstrate an effect of sex (F1,27=10.46; P

Discussion

Animal models of pediatric brain damage have focused on the PN7 rat pup as animals of this age are particularly susceptible to neuronal damage induced by KA, with the CA1 region being the primary site of damage (Cook and Crutcher, 1986). Rat pups less than a week old are generally impervious to the excitotoxic effects of glutamate due to the relatively low expression and functionality of the NMDA and AMPA receptors, the primary mediators of excitotoxicity Liu et al 1996, Wolf and Keilhoff 1984,

References (89)

  • I. Harukuni et al.

    Deleterious effect of B-estradiol in a rat model of transient forebrain ischemia

    Brain Res

    (2001)
  • Z. He et al.

    Proestrus levels of estradiol during transient global ischemia improves the histological outcome of the hippocampal CA1 regionperfusion-dependent and -independent mechanisms

    J Neurol Sci

    (2002)
  • R. Katoh-Semba et al.

    Brain-derived neurotrophic factor, nerve growth and neurotrophin-3 in selected regions of the rat brain following kainic acid-induced seizure activity

    Neurosci Res

    (1999)
  • C.Y. Kuan et al.

    Mechanisms of programmed cell death in the developing brain

    Trends Neurosci

    (2000)
  • Z. Liu et al.

    Age-dependent effects of glutamate toxicity in the hippocampus

    Dev Brain Res

    (1996)
  • J.W. McDonald et al.

    Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system

    Brain Res

    (1988)
  • E.G. McGeer et al.

    Neurotoxins as tools in neurobiology

    Int Rev Neurobiol

    (1981)
  • L.P. Miller et al.

    The ontogeny of excitatory amino acid receptors in the rat forebrain. II. Kainic acid receptors

    Neuroscience

    (1990)
  • T.A. Milner et al.

    Hormonal regulation of axonal sprouting in the hippocampus

    Brain Res

    (1982)
  • R.L. Moss et al.

    Estrogenmechanisms for a rapid action in CA1 hippocampal neurons

    Steroids

    (1999)
  • J.A. O’Keefe et al.

    Transient elevation of estrogen receptors in neonatal rat hippocampus

    Dev Brain Res

    (1990)
  • A.A. Petersen et al.

    Brain-derived neurotrophic factor inhibits apoptosis and dopamine-induced free radical production in striatal neurons but does not prevent cell death

    Brain Res Bull

    (2001)
  • A. Rodriguez-Moreno et al.

    Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus

    Neuron

    (1997)
  • P.J. Shughrue et al.

    Evidence for novel estrogen binding sites in the rat hippocampus

    Neuroscience

    (2000)
  • D.T. Solum et al.

    Localization of estrogen alpha (ER) in pyramidal neurons of the development rat hippocampus

    Dev Brain Res

    (2001)
  • G. Sperk et al.

    Kainic acid-induced seizuresdose-relationship of behavioural, neurochemical and histopathological changes

    Brain Res

    (1985)
  • P. Tandon et al.

    Neuroprotective effects of brain-derived neurotrophic factor in seizures during development

    Neuroscience

    (1999)
  • C.D. Toran-Allerand

    Mechanisms of estrogen action during neural developmentmediation by interactions with the neurotrophins and their receptors?

    J Steroid Biochem

    (1996)
  • C.E. Weaver et al.

    17-β estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors

    Brain Res

    (1997)
  • G. Wolf et al.

    Kainate and glutamate neurotoxicity in dependence on the postnatal development with special reference to hippocampal neurons

    Dev Brain Res

    (1984)
  • J.A. Adams et al.

    Hypoxemic events in spontaneously breathing premature infantsetiologic basis

    Pediatr Res

    (1997)
  • N.J. Alkayed et al.

    Neuroprotective effects of female gonadal steroids in reproductively senescent female rates

    Stroke

    (2000)
  • N.J. Alkayed et al.

    Gender-linked brain injury in experimental stroke

    Stroke

    (1998)
  • I. Azcoitia et al.

    Gonadal hormones affect neuronal vulnerability to excitotoxin-induced degeneration

    J Neurocytol

    (1999)
  • I. Azcoitia et al.

    Estradiol prevents kainic acid-induced neuronal loss in the rat dentate gyrus

    NeuroReport

    (1998)
  • S. Bahn et al.

    Kainate receptor gene expression in the developing rat brain

    J Neurosci

    (1994)
  • N.C. Berchtold et al.

    Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus

    Eur J Neurosci

    (2001)
  • W.G. Brake et al.

    Novel target sites for estrogen action in the dorsal hippocampusan examination of synaptic proteins

    Endocrinology

    (2001)
  • M.L. Campagne et al.

    NMDA and kainate induce internucleosomal DNA cleavage associated with both apoptotic and necrotic cell death in the neonatal rat brain

    Eur J Neurosci

    (1995)
  • P. Campochiaro et al.

    Ontogenetic development of kainate neurotoxicitycorrelates with glutamatergic innervation

    Proc Natl Acad Sci USA

    (1978)
  • D.W. Choi et al.

    The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death

    Annu Rev Neurosci

    (1990)
  • R. Cossart et al.

    GluR5 kainate receptor activation in interneurons increases tonic inhibition of pyramidal cells

    Nat Neurosci

    (1998)
  • O. Dammann et al.

    Maternal intrauterine infection, cytokines and brain damage in the preterm newborn

    Pediatr Res

    (1997)
  • S.R. Datta et al.

    Cellular survival: a play in three Akts

    Genes & Dev

    (1999)
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