Cellular and Molecular NeuroscienceResearch PaperCompensatory network alterations upon onset of epilepsy in synapsin triple knock-out mice

Adult synapsin triple-knockout mice exhibit epilepsy that manifests as generalized tonic-clonic seizures. Because in vitro recordings have shown a reduction in quantal release from inhibitory neurons, an inherent excitation-inhibition imbalance has been hypothesized as the direct culprit for epilepsy in these mice. We critically assessed this hypothesis by examining neurotransmission during the emergence of epilepsy. Using long-term video and telemetric EEG monitoring we found that synapsin triple-knockout mice exhibit an abrupt transition during early adulthood from a seizure-free presymptomatic latent state to a consistent symptomatic state of sensory-induced seizures. Electrophysiological recordings showed that during the latent period larger field responses could be elicited in slices from mutant mice. However, only after the transition to a symptomatic state in the adult mice did evoked epileptiform activity become prevalent. This state was characterized by resistance to the epileptiform-promoting effects of 4-aminopyridine, by marked hypersensitivity to blockage of GABAA receptors, and by the emergence of unresponsiveness to NMDA receptor antagonism, all of which were not observed during the latent period. Importantly, enhancement in inhibitory transmission was associated with upregulation of GAD67 expression without affecting the number of inhibitory neurons in the same brain areas where epileptiform activity was recorded. We therefore suggest that while deletion of the synapsins initially increases cortical network activity, this enhanced excitability is insufficient to elicit seizures. Rather, compensatory epileptogenic mechanisms are activated during the latent period that lead to an additional almost-balanced enhancement of both the excitatory and inhibitory components of the network, finally culminating in the emergence of epilepsy.

▶Precise timing of onset of epilepsy determined for synapsin triple knockout mice. ▶Field responses are enlarged during latent period prior to emergence of symptoms. ▶In vitro epileptiform activity becomes prevalent with the onset of epilepsy. ▶Slices of symptomatic mice are resistant to 4-AP and APV and hypersensitive to BMI. ▶Enhanced excitatory and inhibitory tone is associated with translational changes.