Abstracts

Rationale: Cortical dysplasia (CD) is a common cause of intractable epilepsy in children and adults, but the mechanisms that link this disorder to seizures are poorly understood. We have studied an animal model of CD, in utero irradiation in rats, to better understand this problem. Previously, we have found that the number of inhibitory interneurons are reduced in CD in this model. We have also found that excitatory drive is reduced in cortical interneurons, but inhibitory currents had not been studied in these cells. In this study, we examined both excitatory and inhibitory synaptic activity in a specific subset of interneurons, fast-spiking (FS), parvalbumin (PV)-containing neurons. Methods: Pregnant rats were exposed to 225 cGy of external radiation from a linear accelerator source. At age P28-P32, offspring were sacrificed for testing. Coronal slices (300 microns thick) were obtained from the somatosensory cortex. FS cells in layer IV of controls and the middle region of irradiated animals were identified based on location, morphology, and intrinsic firing properties using IR-DIC microscopy. Whole cell recordings in voltage clamp configuration were used to obtain spontaneous and miniature EPSCs and IPSCs. Stimulus-evoked IPSCs were also recorded to examine short-term plasticity (STP) of these currents using 5-pulse trains at 10 Hz. In some experiments, biocytin-filled neurons were processed for histology and treated with a monoclonal antibody for PV. Results: FS cells showed a variety of soma shapes but multipolar cells predominated. Of successfully recovered, biocytin-injected cells, 12 of 16 controls and 7 of 10 cells from dysplastic cortex were PV-immunoreactive. With glutamatergic transmission blocked, both spontaneous and miniature IPSCs were reduced in frequency, but not amplitude, in FS interneurons from dysplastic cortex compared to controls. STP studies demonstrated short-term depression of IPSCs in controls and short-term facilitation in CD. In conditions where EPSCs and IPSCs could be recorded simultaneously from individual FS interneurons, the ratio of EPSC to IPSCs frequency was lower in CD compared to controls. This was true for both spontaneous and miniature currents. Conclusions: FS cells in CD show a reduced frequency of sIPSCs and mIPSCs. This could be due to a reduction in the number of inhibitory terminals on those cells, a reduction in release probability in the terminals, or a combination of both. Even though the frequency of both EPSCs and IPSCs are reduced in FS cells in dysplastic cortex, the EPSCs are more severely affected such that the balance of excitation and inhibition favors in inhibition in these cells. We predict that this would result in FS interneurons that are less active and less able to respond to periods of increased excitatory activity. These studies elucidate another way that inhibition is impaired in dysplastic cortex in the irradiated rat model. Similar mechanisms may contribute to epileptogenesis in some forms of human CD.