Abstracts

Rationale: Patients with generalized epilepsy syndromes often experience different types of generalized seizures that have distinct electrographic and behavioral characteristics. Sometimes, the expression of one type of generalized seizure evolves into another. It is not known if these different seizure types activate separate or overlapping brain networks, or how the occurrence of one seizure type may affect the expression of others. Determining the interactions among cerebral networks that participate in different types of generalized seizures is critical to understand their epileptogenic mechanisms and for the development of potential network-specific therapies (e.g. neurostimulation). Recently, we developed a mouse that contains a human juvenile myoclonic epilepsy mutation, [Gabra1(A322D)], and showed that Gabra1+/A322D mice experience both absence and myoclonic seizures. Here, using Gabra1+/A322D mice, we determined if absence and myoclonic seizures activate an overlapping sensorimotor cortical network and whether repetitive absence seizures alter myoclonic seizures and excitatory synaptic currents. Methods: Gabra1+/A322D mice were implanted with multiple EEG electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices. We recorded absence and myoclonic seizures and employed linear and nonlinear analyses to identify regions of initial ictal activation in the sensorimotor cortex. Next, we pharmacologically evoked repetitive absence seizures by administering a single interperitoneal injection of ?-butyrolactone (GBL). After recovery and GBL elimination, we determined the effects of the prior repetitive absence seizures on myoclonic seizure frequency. Finally, patch clamp electrophysiology studies on layer VI S1 pyramidal neurons from control and GBL-treated mice were used to determine the effects of prior repetitive absence seizures on excitatory postsynaptic currents (EPSCs). Results: Surprisingly, we found that the spatiotemporal dynamics of sensorimotor cortex activation is similar in both absence and myoclonic seizures with spikes appearing in S1 2-5 ms prior to aM1 (P < 0.05). However, absence and myoclonic seizure ictal spikes differ with the absolute voltage of myoclonic seizure spikes being significantly higher than that of absence seizure spikes (P < 0.01) and with a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two absence seizure spikes (P < 0.05). Moreover, a significantly greater fraction of myoclonic seizure spikes are initially localized to only an S1 electrode (P < 0.01). Prior repetitive absence seizures increase myoclonic seizures by approximately two-fold. In addition, prior repetitive absence seizures raise S1 neuronal excitability with EPSC amplitudes increased from 16 3 pA to 23 1 pA (P < 0.05 ) but do not alter EPSC frequency or the time course of EPSC kinetics. Conclusions: These data indicate that absence and myoclonic seizures engage overlapping networks in sensorimotor cortex but that, relative to absence seizures, myoclonic seizures are associated with increased cortical excitation and a more focal initial activation in S1. Moreover, repetitive absence seizures may modulate the expression of myoclonic seizures by altering synaptic plasticity and thereby increasing cortical excitability. Funding: NINDS R01-NS064286 to MJG