Kainate receptors are critical for permissivity to sustained, disorganized and network-wide pathological activity in the epileptic dentate gyrus

In temporal lobe epilepsy, the dentate gyrus (DG) undergoes extensive reorganization through recurrent mossy fiber (rMF) sprouting, engaging both AMPA and kainate receptors (KARs) at granule cell-granule cell (GC-GC) synapses. While KARs are known to enhance neuronal excitability, their specific contribution to epileptogenic rMF network dynamics remains poorly understood. Here, building and assessing a DG network model endowed with KARs, we revealed that slow KAR-EPSPs - which synergistically interacted with persistent sodium currents - profoundly reshaped epileptogenic dynamics by lowering the threshold for pathological activity, through two complementary mechanisms. Regarding structural constraints on the network, KARs reduced the number of sprouted connections required to drive epileptiform discharges. Concerning functional constraints on DG inputs, KARs extended the window for temporal integration, increased network responsiveness, enabling aberrant activities in response to more dispersed input patterns. Actually, the extension of the structural and functional parameter region driving epileptiform activity was effective both for their initiation and, critically, their sustained maintenance. Moreover, KARs drove a striking transition in network behavior, from partially organized collective dynamics to a highly disordered regime. Notably, in the presence of KARs, firing massively invaded the DG network, disorganizing spiking patterns, which resulted in increased dimensionality and entropy of activity, and a drop of mutual information between neurons. Altogether, our results suggest that KARs are not merely amplifiers of network excitation but rather represent consubstantial determinants that fundamentally alter the dynamical landscape, rendering sprouted dentate gyrus network permissive to self-sustaining pathological activity.