Characterization of Neuronal Migration Disorders in Neocortical Structures. II. Intracellular In Vitro Recordings

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.

Functional Magnetic Resonance Imaging and Somatosensory Evoked Potentials in Rats With a Neonatally Induced Freeze Lesion of the Somatosensory Cortex

“…There was some evidence for an increased activation in the unaffected, contralateral hemisphere, as postulated from the in vitro experiments (Chevassus-au-Louis et al, 1999;Jacobs et al, 1996;Luhmann and Raabe, 1996;Luhmann et al, 1998b). Still, the dominant findings of our study were (1) absence of obvious neurologic deficits, and (2) highly reduced activation (fMRI and SSEPs) in the lesioned hemisphere.…”

“…Although the amount of tissue is reduced as well, previous in vitro slice studies revealed enhanced rather than decreased excitability of the malformed cortex and the surrounding tissue (Jacobs et al, 1996;Luhmann and Raabe, 1996;Luhmann et al, 1998b). Therefore, reasons other than mere tissue loss must account for the reduced activation found in the present study.…”

“…This hyperexcitability results from an imbalance between excitatory and inhibitory synaptic transmission (Luhmann et al, 1998a). Such an imbalance is further supported by quantitative receptor autoradiography (Zilles et al, 1998) showing an increased binding to NMDA and AMPA receptors and a reduced binding to GABA A and GABA B receptors in the dysplastic cortex.…”

Immunohistochemical Study of Acute Effects of Ethanol on Midbrain of Wistar Rats Associated with the Date of Birth of Neurons in Encephalon

“…The development of the neural system involves a series of time and space dependent events, being related to the date of birth of the neurons and their interaction with the radial glia (Wilsnack et al, 1984;Chevassus-Au-Louis et al, 1998;Luhmann et al, 1998;Redecker et al, 1998;VelezDomingues, 1998;Aversi-Ferreira et al, 2004;AversiFerreira et al, 2005;Aversi-Ferreira et al, 2006, AversiFerreira & Nascimento, 2008.…”

The relationship between schizophrenia and epilepsy: the history and current state of the problem

“…В связи с этим выделяют расстройства нейрональной миграции -врожденные структурные ано-малии развития головного мозга, а также признаки синап-тической регенерации [69]. Эти данные указывают, что шизофреноподобный психоз при эпилепсии может быть связан как с де-, так и регенеративными изменениями в мозге, которые могут быть результатом нарушения разви-тия ЦНС или генетического дефекта [70].…”