Altered Dynamics of Canonical Feedback Inhibition Predicts Increased Burst Transmission in Chronic Epilepsy

Inhibitory interneurons, organized into canonical feedforward and feedback motifs, play a key role in controlling normal and pathological neuronal activity. We demonstrate prominent quantitative changes in the dynamics of feedback inhibition in a rat model of chronic epilepsy (male Wistar rats). Systematic interneuron recordings revealed a large decrease in intrinsic excitability of basket cells and oriens-lacunosum moleculare interneurons in epileptic animals. Additionally, the temporal dynamics of interneuron recruitment by recurrent feedback excitation were strongly altered, resulting in a profound loss of initial feedback inhibition during synchronous CA1 pyramidal activity. Biophysically constrained models of the complete feedback circuit motifs of normal and epileptic animals revealed that, as a consequence of altered feedback inhibition, burst activity arising in CA3 is more strongly converted to a CA1 output. This suggests that altered dynamics of feedback inhibition promote the transmission of epileptiform bursts to hippocampal projection areas.SIGNIFICANCE STATEMENT We quantitatively characterized changes of the CA1 feedback inhibitory circuit in a model of chronic temporal lobe epilepsy. This study shows, for the first time, that dynamic recruitment of inhibition in feedback circuits is altered and establishes the cellular mechanisms for this change. Computational modeling revealed that the observed changes are likely to systematically alter CA1 input-output properties leading to (1) increased seizure propagation through CA1 and (2) altered computation of synchronous CA3 input.