Abstracts

Rationale: Cortical dysplasia (CD) is associated with severe epilepsy in humans and we have used in utero irradiation of fetal rats as an injury-based model of CD. These animals show a selective loss of inhibitory interneurons in the affected cortex with a corresponding reduction in synaptic inhibition in pyramidal neurons. Prior studies have shown that surviving fast-spiking interneurons have a reduction in glutamatergic and GABAergic synaptic input; but that the glutamatergic synapses are more severely affected so that there is an imbalance in excitatory-to-inhibitory input that favors inhibition. The current study was undertaken to see how alterations in synaptic input would affect spontaneous action potentials in three types of interneurons in dysplastic cortex. Methods: Pregnant rats were either sham-irradiated or irradiated with 225 cGy of external X-rays from a linear accelerator source. Coronal slices were obtained from somatosensory cortex at P28-36. We obtained cell-attached recordings from somatostatin (SST)-, parvalbumin (PV)-, and calretinin (CR)-immunoreactive (ir) interneurons in layer IV of controls and the middle region of irradiated animals and quantified spontaneous firing based on frequency and a measure regularity, the co-efficient of variation of the inter-spike interval (CV-ISI). Following cell-attached recordings, the same cells were studied in whole-cell configuration to quantify excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs). Results: SST- and PV-ir interneurons fired less frequently and with less regularity than controls (Table 1). This corresponded to a relative imbalance in the ratio of EPSCs to IPSCs that favored inhibition (Table 2). In contrast, CR-ir interneurons from CD showed no differences in firing rate or regularity compared to controls. These interneurons showed a normal ratio of EPSCs to IPSCs. Additional studies were performed to examine the effects of pharmacological blockade of glutamatergic and GABAergic transmission on firing rates and regularity. In the presence of glutamatergic and GABAergic blockers, SST- and PV-ir interneurons in CD were no different from controls based on firing rates and CV-ISI. Conclusions: These findings demonstrate that the relative balance of excitatory and inhibitory synaptic input exerts powerful influence over spontaneous activity of cortical interneurons and that pathological alterations in this balance can impair the normal function of these cells. Specifically, the shift towards predominance of inhibitory input in irradiated rats causes a relative quiescence of SST- and PV-ir interneurons. This may have a significant impact on cortical inhibition in these animals and may be an important mechanism of epileptogenesis. These same mechanisms may also relevant in some forms of CD-associated epilepsy in humans.