Friscourt, F. | bioRxiv Science

bioRxiv2026

Progressive bilateral recruitment and resilient network reorganization during temporal lobe epilepsy

BackgroundTemporal lobe epilepsy (TLE) often originates from focal hippocampal injury but progressively evolves into a bilateral epileptic network engaging both hippocampi and distributed cortical regions. A mechanistic understanding of how this network emerges, and whether early perturbation of specific nodes can alter its trajectory, is essential for developing network-level therapeutic strategies. ObjectiveWe used a kainate-induced rodent model of TLE to (1) characterize the spatiotemporal emergence of epileptic discharges during the latent phase, (2) determine how bilaterally synchronized events develop, and (3) test whether transient chemogenetic silencing of either the ipsilateral epileptogenic focus (EF) or the contralateral hippocampus (CH) modifies large-scale epileptogenesis. MethodsFreely moving mice were implanted with multi-site electrodes spanning bilateral hippocampal subfields (dentate gyrus, CA1, subiculum) and cortical regions (M2, Cg1, PrL, V1, entorhinal cortex). Longitudinal LFP recordings were performed every other day during the latent and early chronic phases following KA or saline injection. DREADD-based chemogenetic inhibition of glutamatergic neurons was applied between days 2-7 post-KA. Epileptiform events were quantified via spike rates, waveform metrics, high-frequency oscillations (HFOs), and short-latency interregional co-spiking ResultsEarly after KA, epileptic spiking emerged locally in the ipsilateral dentate gyrus and progressively organized into HFO-coupled discharges. Contralateral hippocampal recruitment followed a distinctive biphasic time course, characterized by transient early activation, subsequent suppression, and later re-emergence with increasing bilateral coactivation. Cortical regions gradually developed higher spike rates and enhanced DG-related co-spiking, indicating large-scale network integration. Ipsilateral silencing modified local spike composition but did not prevent global network progression, whereas contralateral silencing accelerated ipsilateral epileptogenesis and strengthened pathological HFO expression. ConclusionEpileptogenesis in the KA model reflects a transition from a focal hippocampal insult to a resilient, bilateral cortico-hippocampal network. Targeting a single hippocampal node--even at early latent stages--is insufficient to halt this progression, highlighting the need for network-level therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/701979v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@171797dorg.highwire.dtl.DTLVardef@df13d3org.highwire.dtl.DTLVardef@18e9594org.highwire.dtl.DTLVardef@1fe68f8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2023

Involvement of remote regions in sustained, but not transient, epileptic activities in the kainate mouse model of temporal lobe epilepsy

Animal and human studies have shown that the seizure-generating region is vastly dependent on distant neuronal hubs that can decrease duration and propagation of ongoing seizures. However, we still lack a comprehensive understanding of the impact of distant brain areas on specific interictal or ictal epileptic activities (e.g., isolated spikes, spike trains, seizures). Such knowledge is critically needed since all kinds of epileptic activities are not equivalent in terms of clinical expression and impact on the progression of the disease. We used surface, high-density EEG and multisite intracortical recordings, combined with pharmacological silencing of specific brain regions in the well-known kainate mouse model of temporal lobe epilepsy. We tested the impact of selective regional silencing on the generation of epileptic activities within a continuum ranging from very transient to more sustained and long-lasting discharges reminiscent of seizures. Silencing the contralateral hippocampus completely suppresses sustained ictal activities in the focus, as efficiently as silencing the focus itself, but while focus silencing abolishes all focal activities, contralateral silencing fails to control transient spikes. In parallel, we observed that sustained epileptic discharges in the focus are preceded by contralateral firing and more strongly phase locked to bi-hippocampal delta/theta oscillations than transient spiking activities, reinforcing the presumed dominant role of the contralateral hippocampus in promoting long-lasting, but not transient, epileptic activities. Altogether, our work provides suggestive evidence that the contralateral hippocampus is necessary for the interictal-to ictal-state transition and proposes that cross-talk between contralateral neuronal activity and ipsilateral delta/theta oscillation could be a candidate mechanism underlying the progression from short to long-lasting epileptic activities. Key PointsO_LIWe study how regions remote from the focus influence epileptic activities in the kainate mouse model of temporal lobe epilepsy. C_LIO_LIThe contralateral hippocampus plays a decisive role in the initiation of sustained epileptic activities C_LIO_LIIntegration of contralateral activities and bi-hippocampal delta/theta oscillations precedes focal paroxysmal activities C_LIO_LIWe propose that a large-scale epileptic network might be necessary for the transition from interictal to ictal states C_LI

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