Competing routes back to firing shape population hyperexcitability and its selective suppression

Abstract

Whether a neuron will fire again is fundamentally a different question from whether a quiescent neuron will activate. Even within the same neuron, successive spikes can follow distinct post-spike trajectories, with after-depolarization permitting early return to firing and depolarization block prolonging inactivity. Therefore, we propose that hyperexcitability involves changes in the opportunities to fire again across the spike cycle, and not just from quiescence. The firing hazard makes these opportunities measurable: in whole-cell recordings of midbrain dopamine neurons, the subthreshold voltage trough resolves a non-monotone aggregate firing hazard into physiologically distinguishable components. We represent these components as competing return pathways within a population renewal model and show that they lead to heterogeneous firing patterns within a single neuronal population subject to a common drive. An immediate-return pathway provides an early opportunity to fire by skipping some stages of recovery, and promotes population hyperexcitability independent of quiescent activation. Conversely, a sequestration pathway diverts recently active neurons into a prolonged non-recruitable state, representing depolarization block or use-dependent blockade. Pharmacological selectivity of anti-seizure medications such as phenytoin and carbamazepine arises from the redistribution of neurons among return pathways at every renewal, with fast-cycling pathological regimes providing more opportunities for renewal and eventual sequestration.