Epilepsy Impairs In Vitro Thalamic Signal Processing

Background: Autism spectrum disorders (ASD) are often associated with subclinical epileptiform discharge (Chez et al. 2006; Hara et al. 2007) and epilepsy correlated with behavioral regression (Humphrey et al. 2006; Jian et al. 2006). These cortical discharges intensely activate thalamus (Blumenfeld et al. 2004; Enev et al. 2007). Since ASD individuals show impaired rapid sensory processing (Tallal and Piercy, 1973; Oram Cardy et al. 2005), we hypothesized that some ASD might result from excessive cortical excitation of thalamus triggering homeostatic changes in thalamus that impair sensory-motor signal processing.

Objectives: Evaluate effects of chronic infantile epilepsy (stargazer, JAXS) and acute epileptiform discharge (pilocarpine) on thalamocortical neuron firing properties and plasma membrane ion currents.

Methods: Studied were performed on mice (2-4 months old) as previously described (Kasten et al., 2007). In coronal brain slices (230-280 mm), single thalamocortical neurons were visualized using infrared DIC optics. Whole-cell patch-clamp recording performed in current or voltage clamp mode.

Results: First, we found rapid phasic and burst firing were impaired, while prolonged firing (> 1 sec) is preserved in thalamic relay neurons of these two distinct mouse models of epilepsy. Second, fast transient K+ currents (< 50 msec) were increased explaining the selective defect in rapid and burst firing. Third, a dominant negative LGI1 (leucine-rich glioma-inactivated) blocked the increase of K+ current.

Conclusions: We define a molecular pathway involving a protein secreted at glutamate synapses, LGI1, and a transient A-type K+ current that mediate epilepsy-induced impairments of rapid signal processing in thalamus. The studies establish a new model of ASD pathogenesis where cortical epileptiform discharges trigger a reversible defect of thalamic sensory-motor signal processing.