Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings

J Neurophysiol. 1998 Jul;80(1):92-102. doi: 10.1152/jn.1998.80.1.92.

Abstract

Neuronal migration disorders (NMD) are involved in a variety of different developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dysplastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebral cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in cortical slices from adult sham-operated rats revealed normal passive and active intrinsic membrane properties and normal stimulus-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively). Regular spiking neurons recorded in rat dysplastic cortex showed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relationship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of multiphasic burst discharges, which coincided with extracellular field potentials and lasted 150-800 ms. These epileptiform responses could be recorded at membrane potentials between -50 and -110 mV and were blocked by -2-amino-5-phosphonovaleric acid (APV), indicating the involvement of N-methyl--aspartate (NMDA) receptors. Isolated NMDA-mediated and APV-sensitive EPSPs could be recorded at membrane potentials negative to -70 mV, suggesting that NMDA receptors are activated at relatively negative membrane potentials. In comparison with the controls, polysynaptic IPSPs mediated by the gamma-aminobutyric acid (GABA) type A and B receptor were either absent or reduced in peak conductance in microgyric cortex by 27% (P < 0.05) and 17%, respectively. However, monosynaptic IPSPs recorded in the presence of ionotropic glutamate receptor antagonists revealed a similar efficacy in NMD and control cortex, indicating that GABAergic neurons in microgyric cortex get a weaker excitatory input. Our data indicate that the expression of epileptiform activity in NMD-affected cortex rather results from an imbalance between excitatory and inhibitory synaptic transmission than from alterations in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor-mediated excitation in pyramidal neurons and a concurrent decrease of glutamatergic input onto inhibitory interneurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Aging / physiology
  • Animals
  • Animals, Newborn
  • Brain Diseases / physiopathology
  • Cell Movement / physiology*
  • Evoked Potentials / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • In Vitro Techniques
  • Interneurons / physiology
  • Membrane Potentials / drug effects
  • Neocortex / abnormalities*
  • Neocortex / growth & development
  • Neocortex / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Pyramidal Cells / physiology
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Synapses / drug effects
  • Synapses / physiology
  • Synaptic Transmission / drug effects

Substances

  • Excitatory Amino Acid Antagonists
  • Quinoxalines
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • 2-Amino-5-phosphonovalerate