Altered glutamate receptor - transporter expression and spontaneous seizures in rats exposed to methylazoxymethanol in utero.
OBJECTIVE
Brain malformations are a common cause of intractable epilepsy and cognitive dysfunction in children. Prenatal exposure to the teratogen methylazoxymethanol (MAM) is a rodent model of brain malformation featuring loss of lamination, clusters of displaced hippocampal cells, and pharmaco-resistance to antiepileptic drugs. In a normotopic hippocampus, expression of postsynaptic glutamate receptors and the transporters regulating neurotransmitter reuptake are critical factors modulating excitation and synaptic communication. Alterations in this system can have profound effects on overall excitability, cognitive function, and seizure thresholds.


METHODS
Immunohistochemical techniques were used to analyze the expression of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5 methylisoxazole-4-proprionic acid (AMPA) receptor subunits in rats exposed to MAM in utero (25 mg/kg, intraperitoneal injection). We also examined the expression of several glutamate transporters (EAAC1, vGLUT1, and vGLUT2). A video-electroencephalographic (video-EEG) system was used for long-term monitoring of adult MAM-exposed rats.


RESULTS
Heterotopic hippocampal neurons exhibited striking reductions in GluR1 and EAAC1 expression; vGlut2 expression was prominent in these regions. Spontaneous electrographic seizures were verified in two animals.


CONCLUSIONS
We conclude that glutamate receptor subunit and transporter expression are altered in animals exposed to MAM in utero. Further studies in the MAM model may provide greater insight into the potential disruptions in excitatory synaptic neurotransmission that can occur in a malformed brain.
Harrington
Emily P
EP
Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, California 94143, USA.
Möddel
Gabriel
G
Najm
Imad M
IM
Baraban
Scott C
SC
D027322:Amino Acid Transport System X-AG / Q000187:drug effects / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D002828:Choristoma / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000706:statistics & numerical data; D005260:Female; D006624:Hippocampus / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008431:Maternal-Fetal Exchange; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D013723:Teratogens / Q000494:pharmacology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C493475:Slc17a6 protein, rat; D013723:Teratogens; D050599:Vesicular Glutamate Transport Protein 2; D008746:Methylazoxymethanol Acetate; C030667:methylazoxymethanol