Downmodulation of Potassium Conductances Induces Epileptic Seizures in Cortical Network Models Via Multiple Synergistic Factors.

Voltage-gated potassium conductances play a critical role not only in normal neural function, but also in many neurological disorders and related therapeutic interventions. In particular, in an important animal model of epileptic seizures, 4-aminopyridine (4-AP) administration is thought to induce seizures by reducing in cortex and other brain areas. Interestingly, 4-AP has also been useful in the treatment of neurological disorders such as multiple sclerosis and spinal cord injury, where it is thought to improve action potential propagation in axonal fibers. Here, we examined downmodulation in biophysical models of cortical networks that included different neuron types organized in layers, potassium diffusion in interstitial and larger extracellular spaces, and glial buffering. Our findings are fourfold. First, downmodulation in pyramidal and fast-spiking inhibitory interneurons led to differential effects, making the latter much more likely to enter depolarization block. Second, both neuron types showed an increase in the duration and amplitude of action potentials, with more pronounced effects in pyramidal neurons. Third, a sufficiently strong reduction dramatically increased network synchrony, resulting in seizure-like dynamics. Fourth, we hypothesized that broader action potentials were likely to not only improve their propagation, as in 4-AP therapeutic uses, but also to increase synaptic coupling. Notably, graded-synapses incorporating this effect further amplified network synchronization and seizure-like dynamics. Overall, our findings elucidate different effects that downmodulation may have in cortical networks, explaining its potential role in both pathological neural dynamics and therapeutic applications.