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

Abstract In temporal lobe epilepsy, the dentate gyrus (DG) undergoes extensive reorganization through recurrent mossy fiber (rMF) sprouting, involving both AMPA and kainate receptors (KARs) at granule cell-to-granule cell (GC-GC) recurrent synapses. While KARs are known to enhance neural excitability, their specific contribution to the dynamics of the epileptogenic GC-GC network remains poorly understood. Here, by building and assessing a DG network model endowed with KARs, we revealed that the slow excitatory postsynaptic potentials (EPSPs) they mediate, in synergy with persistent sodium currents, profoundly reshape epileptogenic dynamics by facilitating the conditions for pathological activity, through two complementary mechanisms. Regarding input processing, KARs extended the window for temporal integration in GCs, favoring the initiation of network aberrant activities in response to more dispersed input patterns. Concerning network interactions, KARs reduced the number of sprouted connections needed for the development of epileptiform discharges. In fact, 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 behaviour, from partially organized collective dynamics to a highly disordered regime. In their presence, massive firing propagated through the DG network, disrupting spatial and temporal spiking patterns. This resulted in increased activity dimensionality and entropy, together with reduced mutual information between neurons. Altogether, our results suggest that KARs are not merely amplifiers of network excitation but critical determinants that fundamentally reshape the dynamical landscape, rendering the sprouted DG network permissive to self-sustaining pathological activity. Competing Interest Statement The authors have declared no competing interest. Footnotes This revised manuscript includes improvements to enhance clarity and readability. The discussion section has also been expanded to provide deeper insights into the study's implications. The scientific content and conclusions remain unchanged.