Downmodulation of potassium conductances induces epileptic seizures in cortical network models via multiple synergistic factors

Voltage-gated potassium conductances [Formula: see text] 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 [Formula: see text] in cortex and other brain areas. Interestingly, 4-AP has also been useful in the treatment of neurological disorders such as multiple sclerosis (MS) and spinal cord injury, where it is thought to improve action potential propagation in axonal fibers. Here, we examined [Formula: see text] downmodulation in bio-physical 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, [Formula: see text] 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 [Formula: see text] 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 [Formula: see text] downmodulation may have in cortical networks, explaining its potential role in both pathological neural dynamics and therapeutic applications.Significance Statement The modulation of voltage-gated potassium-conductances [Formula: see text] is thought to play an important role in epileptic seizures and therapeutic interventions in epilepsy, multiple sclerosis and spinal-cord injury. We show that [Formula: see text] downmodulation can lead to a cascade of effects including changes in basal excitability, broadening of action potentials resulting in enhanced robustness to synaptic noise perturbations and strengthening of synaptic coupling; and differential effects in excitatory and fast-spiking inhibitory interneurons, promoting depolarization block in the latter under high downmodulation. All these effects synergistically contribute to the emergence of seizure-like dynamics in the form of almost-periodic synchronized neuronal-population spiking in cortical networks. Under appropriate levels, [Formula: see text] downmodula tion can also have therapeutic effects by improving neuronal communication via the broadening of action potentials.