CHARACTERIZATION OF NEURONAL MIGRATION DISORDERS IN NEOCORTICAL STRUCTURES - II - INTRACELLULAR IN-VITRO RECORDINGS

Neuronal migration disorders (NMD) are involved in a variety of differ ent developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dys plastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebra l cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in c ortical slices from adult sham-operated rats revealed normal passive a nd active intrinsic membrane properties and normal stimulus-evoked exc itatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respe ctively). Regular spiking neurons recorded in rat dysplastic cortex sh owed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relation ship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of mult iphasic burst discharges, which coincided with extracellular field pot entials and lasted 150-800 ms. These epileptiform responses could be r ecorded at membrane potentials between -50 and -110 mV and were blocke d by DL-2-amino-5-phosphonovaleric acid (APV), indicating the involvem ent of N-methyl-D-aspartate (NMDA) receptors. Isolated NMDA-mediated a nd APV-sensitive EPSPs could be recorded at membrane potentials negati ve to -70 mV, suggesting that NMDA receptors are activated at relative ly negative membrane potentials. In comparison with the controls, poly synaptic IPSPs mediated by the gamma-aminobutyric acid (GABA) type A a nd B receptor were either absent or reduced in peak conductance in mic rogyric cortex by 27% (P < 0.05) and 17%, respectively. However, monos ynaptic IPSPs recorded in the presence of ionotropic glutamate recepto r antagonists revealed a similar efficacy in NMD and control cortex, i ndicating that GABAergic neurons in microgyric cortex get a weaker exc itatory input. Our data indicate that the expression of epileptiform a ctivity in NMD-affected cortex rather results from an imbalance betwee n excitatory and inhibitory synaptic transmission than from alteration s in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor-mediated excitation in pyramidal neurons an d a concurrent decrease of glutamatergic input onto inhibitory interne urons.