Sensitivity of unilateral- versus bilateral-onset spike-wave discharges to ethosuximide and carbamazepine in the fluid percussion injury rat model of traumatic brain injury.

Unilateral-onset spike-wave discharges (SWDs) following fluid percussion injury (FPI) in rats have been used for nearly two decades as a model for complex partial seizures in human posttraumatic epilepsy (PTE). This study determined if SWDs with a unilateral versus bilateral cortical onset differed. In this experiment, 2-mo-old rats received severe FPI (3 atm) or sham surgery and were instrumented for chronic video-electrocorticography (ECoG) recording (up to 9 mo). The antiseizure drug, carbamazepine (CBZ), and the antiabsence drug, ethosuximide (ETX), were administered separately to determine if they selectively suppressed unilateral- versus bilateral-onset SWDs, respectively. SWDs did not significantly differ between FPI and sham rats on any measured parameter (wave-shape, frequency spectrum, duration, or age-related progression), including unilateral (∼17%) versus bilateral (∼83%) onsets. SWDs with a unilateral onset preferentially originated ipsilateral to the craniotomy in both FPI and sham rats, suggesting that the unilateral-onset SWDs were related to surgical injury and not specifically to FPI. ETX profoundly suppressed SWDs with either unilateral or bilateral onsets, and CBZ had no effect on either type of SWD. These results suggest that SWDs with either a unilateral or bilateral onset have a pharmacosensitivity similar to absence seizures and are very different from the complex partial seizures of PTE. Therefore, SWDs with a unilateral onset after FPI are not a model of the complex partial seizures that occur in PTE, and their use for finding new treatments for PTE could be counterproductive, particularly if their close similarity to normal brain oscillations is not acknowledged.NEW & NOTEWORTHY Unilateral-onset spike-wave discharges (SWDs) in rats have been used to model complex partial seizures in human posttraumatic epilepsy (PTE), compared to bilateral-onset SWDs thought to reflect human absence seizures. Here, we show that both unilateral- and bilateral-onset SWDs following traumatic brain injury are suppressed by the antiabsence drug ethosuximide and are unaffected by the antiseizure drug carbamazepine. We propose that unilateral-onset SWDs are not useful for studying mechanisms of, or treatments for, PTE.

Effects of immunization with heat-killed Mycobacterium vaccae on autism spectrum disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy.

Autism spectrum disorders (ASDs) and epilepsy are often comorbid. The basis for this co-occurrence remains unknown; however, inflammatory stressors during development are a shared risk factor. To explore this association, we tested the effect of repeated immunizations using a heat-killed preparation of the stress-protective immunoregulatory microbe Mycobacterium vaccae NCTC 11,659 (M. vaccae) on the behavioral and epileptogenic consequences of the combined stress-terbutaline (ST) rat model of ASD-like behavior/epilepsy. Repeated immunization of the dam with M. vaccae during pregnancy, followed by immunization of the pups after terbutaline injections, prevented the expression of ASD-like behavior but did not appear to protect against, and may have even enhanced, the spontaneous epileptogenic effects of ST. Maternal M. vaccae injections transferred an anti-inflammatory immunophenotype to offspring, and repeated injections across development prevented ST-induced increases in microglial density at early developmental time points in a region-specific manner. Despite epidemiological comorbidity between ASD/epileptic conditions and shared environmental risk factors, our results suggest that the expression of ASD-like behaviors, but perhaps not epileptogenesis, is sensitive to early anti-inflammatory intervention. These data provide support for the exploration of immunoregulatory strategies to prevent the negative neurodevelopmental behavioral effects of stressors during early critical periods.

Progression of convulsive and nonconvulsive seizures during epileptogenesis after pilocarpine-induced status epilepticus.

Although convulsive seizures occurring during pilocarpine-induced epileptogenesis have received considerable attention, nonconvulsive seizures have not been closely examined, even though they may reflect the earliest signs of epileptogenesis and potentially guide research on antiepileptogenic interventions. The definition of nonconvulsive seizures based on brain electrical activity alone has been controversial. Here we define and quantify electrographic properties of convulsive and nonconvulsive seizures in the context of the acquired epileptogenesis that occurs after pilocarpine-induced status epilepticus (SE). Lithium-pilocarpine was used to induce the prolonged repetitive seizures characteristic of SE; when SE was terminated with paraldehyde, seizures returned during the 2-day period after pilocarpine treatment. A distinct latent period ranging from several days to >2 wk was then measured with continuous, long-term video-EEG. Nonconvulsive seizures dominated the onset of epileptogenesis and consistently preceded the first convulsive seizures but were still present later. Convulsive and nonconvulsive seizures had similar durations. Postictal depression (background suppression of the EEG) lasted for >100 s after both convulsive and nonconvulsive seizures. Principal component analysis was used to quantify the spectral evolution of electrical activity that characterized both types of spontaneous recurrent seizures. These studies demonstrate that spontaneous nonconvulsive seizures have electrographic properties similar to convulsive seizures and confirm that nonconvulsive seizures link the latent period and the onset of convulsive seizures during post-SE epileptogenesis in an animal model. Nonconvulsive seizures may also reflect the earliest signs of epileptogenesis in human acquired epilepsy, when intervention could be most effective. NEW & NOTEWORTHY Nonconvulsive seizures usually represent the first bona fide seizure following a latent period, dominate the early stages of epileptogenesis, and change in severity in a manner consistent with the progressive nature of epileptogenesis. This analysis demonstrates that nonconvulsive and convulsive seizures have different behavioral outcomes but similar electrographic signatures. Alternatively, epileptiform spike-wave discharges fail to recapitulate several key seizure features and represent a category of electrical activity separate from nonconvulsive seizures in this model.

Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model.

Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome.