Altered dynamics of canonical feed-back inhibition predicts increased burst transmission in chronic epilepsy.

Inhibitory interneurons, organized into canonical feed-forward and feed-back motifs, play a key role in controlling normal and pathological neuronal activity. We demonstrate prominent quantitative changes in the dynamics of feed-back 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 OLM interneurons in epileptic animals. Additionally, the temporal dynamics of interneuron recruitment by recurrent feed-back excitation was strongly altered, resulting in a profound loss of initial feed-back inhibition during synchronous CA1 pyramidal activity. Biophysically constrained models of the complete feed-back circuit motifs of normal and epileptic animals revealed that as a consequence of altered feed-back inhibition, burst activity arising in CA3 is more strongly converted to a CA1 output. This suggests that altered dynamics of feed-back 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 modelling revealed that the observed changes are likely to systematically alter CA1 input-output properties leading to i) increased seizure propagation through CA1 and ii) altered computation of synchronous CA3 input.