Altered receptor subunit expression in rat neocortical malformations.
OBJECTIVE
Identification of changes in neurotransmitter function in animal models of epilepsy provides a basis for rational drug development and an understanding of the mechanisms underlying epileptogenesis. We investigated changes in the efficacy of the benzodiazepine type I agonist zolpidem and the polyamine site N-methyl-D-aspartate receptor antagonist ifenprodil in a rat model of microgyria.


METHODS
Neonatal freeze lesions were used to produce a microsulcus in the normally lissencephalic rat neocortex with anatomical similarities to human polymicrogyria. Whole-cell voltage-clamp recordings were made from visually identified layer 2/3 pyramidal cells in acutely prepared brain slices from nonlesioned and lesioned rats.


RESULTS
The effect of 20 nmol/L zolpidem on the decay time constant of inhibitory postsynaptic currents was significantly less in neurons from brain slices containing the freeze lesion. A higher concentration (100 nmol/L) of zolpidem was equally efficacious in lesioned and nonlesioned cortex. In lesioned cortex, the threshold for evoking epileptiform discharges was significantly increased in the presence of 10 micromol/L ifenprodil. This effect was significant in both intrinsic hyperexcitability and partial disinhibition with 2 micromol/L bicuculline in lesioned cortex. Ifenprodil had significantly less effect on the threshold of discharges evoked in control cortex in the partial disinhibition model.


CONCLUSIONS
The decreased sensitivity of gamma-aminobutyric acid A receptors to 20 nmol/L zolpidem in the freeze-lesion model is consistent with a delayed or arrested maturation in this animal model. These data support a delay in the developmental switch from alpha2 to alpha1 subunits in gamma-aminobutyric acid A receptors of neocortical pyramidal cells in lesioned cortex. The increased ifenprodil sensitivity of the threshold for evoking epileptiform discharges in both control and disinhibited slices containing the microsulcus is explained by a delay in the expression of the 2A (NR2A) N-methyl-D-aspartate receptor subunit. Delayed development may be a hallmark of this type of cortical dysplasia.
Hablitz
J J
JJ
Department of Neurobiology, University of Alabama at Birmingham, 35294, USA. hablitz@nrc.uab.edu
DeFazio
R A
RA
D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005615:Freezing; D019579:Neocortex / Q000002:abnormalities* / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D000077334:Zolpidem
D010880:Piperidines; D011725:Pyridines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000077334:Zolpidem; C010739:ifenprodil