A single episode of neonatal seizures permanently alters glutamatergic synapses

Authors

  • Brandon J. Cornejo BS,

    1. Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO
    2. Department of Medical Scientist Training Program, University of Colorado, School of Medicine, Denver, CO
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  • Michael H. Mesches PhD,

    1. Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO
    2. Department of Pediatrics, University of Colorado, School of Medicine, Denver, CO
    3. Veterans Affairs Hospital, Denver, CO
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  • Steven Coultrap PhD,

    1. Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO
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  • Michael D. Browning PhD,

    1. Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO
    2. Neuroscience Program, University of Colorado, School of Medicine, Denver, CO
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  • Timothy A. Benke PhD, MD

    Corresponding author
    1. Department of Pharmacology, University of Colorado, School of Medicine, Denver, CO
    2. Department of Pediatrics, University of Colorado, School of Medicine, Denver, CO
    3. Neuroscience Program, University of Colorado, School of Medicine, Denver, CO
    4. Department of Neurology, University of Colorado, School of Medicine, Denver, CO
    • Departments of Pediatrics, Neurology, and Pharmacology, University of Colorado, School of Medicine, Box B-182, 4200 East 9th Avenue, Denver, CO 80262
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Abstract

Objective

The contribution of seizures to cognitive changes remains controversial. We tested the hypothesis that a single episode of neonatal seizures (sNS) on rat postnatal day (P) 7 permanently impairs hippocampal-dependent function in mature (P60) rats because of long-lasting changes at the synaptic level.

Methods

sNS was induced with subcutaneously injected kainate on P7. Learning, memory, mossy fiber sprouting, spine density, hippocampal synaptic plasticity, and glutamate receptor expression and subcellular distribution were measured at P60.

Results

sNS selectively impaired working memory in a hippocampal-dependent radial arm water-maze task without inducing mossy fiber sprouting or altering spine density. sNS impaired CA1 hippocampal long-term potentiation and enhanced long-term depression. Subcellular fractionation and cross-linking, used to determine whether glutamate receptor trafficking underlies the alterations of memory and synaptic plasticity, demonstrated that sNS induced a selective reduction in the membrane pool of glutamate receptor 1 subunits. sNS induced a decrease in the total amount of N-methyl-D-aspartate receptor 2A and an increase in the primary subsynaptic scaffold, PSD-95.

Interpretation

These molecular consequences are consistent with the alterations in plasticity and memory caused by sNS at the synaptic level. Our data demonstrate the cognitive impact of sNS and associate memory deficits with specific alterations in glutamatergic synaptic function. Ann Neurol 2007

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