Characterization of neuronal migration disorders in neocortical structures: Loss or preservation of inhibitory interneurons?

Purpose: Neuronal migration disorders (NMD) are often associated with thera py-resistant epilepsy. In human cerebral cortex, this hyperexcitability has been correlated with a loss of inhibitory interneurons. We used a rat mode l of focal cortical NMD (microgyria) to determine whether the expression of epileptiform activity in this model coincides with a decrease in inhibitor y interneurons. Methods: In 2- to 4-month-old rats, the density of interneurons immunoreact ive for gamma-aminobutyric acid (GABA), calbindin, and parvalbumin was dete rmined in fronto-parietal cortex in nine 200-mu m-wide sectors located up t o 2.5 mm lateral and 2.0 mm medial from the lesion center in primary pariet al cortex (Par1). Quantitative measurements in homotopic areas of age-match ed sham-operated rats served as controls. Results: The freeze lesion performed in newborn rat cortex resulted in adul t rats with a microgyrus extending in a rostrocaudal direction from frontal to occipital cortex. The density of GABA- and parvalbumin-positive neurons in fronto-parietal cortex was not significantly different between lesioned and control animals. Only the density of calbindin-immunoreactive neurons located 1.0 mm lateral and 0.5 mm medial from the lesion was significantly (Student t test, p < 0.05) larger in freeze-lesioned rats (5,817 +/- 562 an d 6,400 +/- 795 cells per mm(3), respectively; n = 12) compared with measur ements in mm homotopic regions in Par1 cortex of controls (4,507 +/- 281 an d 4,061 +/- 319 cells per mm(3), respectively; n = 5). Conclusions: The previously reported widespread functional changes in this model of cortical NMD are not related to a general loss of inhibitory inter neurons. Other factors, such as a decrease in GABA receptor density, modifi cations in GABA, receptor subunit composition, or alterations in the excita tory network, e.g., an increase in the density of calbindin-immunoreactive pyramidal cells, more likely contribute to the global disinhibition and wid espread expression of pathophysiological activity in this model of cortical NMD.