Characterization of neuronal migration disorders in neocortical structures: loss or preservation of inhibitory...

Neuronal migration disorders (NMD) are often associated with therapy-resistant epilepsy. In human cerebral cortex, this hyperexcitability has been correlated with a loss of inhibitory interneurons. We used a rat model of focal cortical NMD (microgyria) to determine whether the expression of epileptiform activity in this model coincides with a decrease in inhibitory interneurons.

In 2-to 4-month-old rats, the density of interneurons immunoreactive for gamma-aminobutyric acid (GABA), calbindin, and parvalbumin was determined in fronto-parietal cortex in nine 200-microm-wide sectors located up to 2.5 mm lateral and 2.0 mm medial from the lesion center in primary parietal cortex (Par1). Quantitative measurements in homotopic areas of age-matched sham-operated rats served as controls.

The freeze lesion performed in newborn rat cortex resulted in adult rats with a microgyrus extending in a rostro-caudal 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 and 6,400 +/- 795 cells per mm3, respectively; n = 12) compared with measurements in homotopic regions in Par1 cortex of controls (4,507 +/- 281 and 4, 061 +/- 319 cells per mm3, respectively; n = 5).

The previously reported widespread functional changes in this model of cortical NMD are not related to a general loss of inhibitory interneurons. Other factors, such as a decrease in GABA receptor density, modifications in GABAA receptor subunit composition, or alterations in the excitatory network, e.g., an increase in the density of calbindin-immunoreactive pyramidal cells, more likely contribute to the global disinhibition and widespread expression of pathophysiological activity in this model of cortical NMD.