A single episode of neonatal seizures permanently alters glutamatergic synapses

• Published in: Annals of neurology Vol. 61; no. 5; pp. 411 - 426
• Main Authors: Cornejo, Brandon J., Mesches, Michael H., Coultrap, Steven, Browning, Michael D., Benke, Timothy A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-05-2007; Willey-Liss
• Subjects: Animals; Animals, Newborn; Biological and medical sciences; Blotting, Western; Cross-Linking Reagents; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dendrites - drug effects; Dendrites - ultrastructure; Disks Large Homolog 4 Protein; Electrophysiology; Excitatory Amino Acid Agonists; Female; Glutamic Acid - physiology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hippocampus - pathology; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kainic Acid; Maze Learning - physiology; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Memory - physiology; Mental Recall - physiology; Mossy Fibers, Hippocampal - pathology; Nervous system (semeiology, syndromes); Neurology; Neuronal Plasticity - physiology; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - genetics; Seizures - chemically induced; Seizures - pathology; Seizures - psychology; Subcellular Fractions - pathology; Synapses - pathology; Human; Neonatal; Synapse; Nervous system diseases; Newborn; Epilepsy; Central nervous system disease; Cerebral disorder
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21071

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