Suppressing cortical glutamatergic neurons produces paradoxical interictal discharges and seizures
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Introduction
Seizures are traditionally attributed to excessive excitation or deficient inhibition, yet recent clinical and slice data show they can also paradoxically arise when inhibition outweighs excitation. We chemogenetically suppressed neocortical glutamatergic neurons to test whether such suppression elicits epileptic activity in vivo.
Methods
CaMKIIα-driven Gi-coupled hM4Di or Gq-coupled hM3Dq Designer Receptor Exclusively Activated by Designer Drug (DREADDs) were expressed in cortical glutamatergic neurons of Rasgrf2-jGCaMP8m and wildtype C57BL/6J mice. Widefield calcium imaging and 32-channel transparent electrocorticography were performed before and after systemic clozapine-N-oxide (CNO; 1.25–5 mg kg ¹).
Results
DREADD activation induced intermittent, large-amplitude, synchronized calcium transients confined to the CaMKIIα-hM4Di focus, accompanied by focal ECoG spikes that persisted for >3 h and sometimes evolved into seizures. By contrast, CNO activation of excitatory neurons via CaMKIIα-hM3Dq DREADDs desynchronized activity without epileptiform discharges. The same process duplicated in wild-type animals provoked similar epileptiform discharges.
Conclusion
Selective suppression of excitation can paradoxically drive cortical networks into hypersynchronous, epileptic states, challenging the simple excess-excitation model of ictogenesis. These findings highlight that seizures may result from relative inhibitory dominance, and that considering this ‘excess inhibition’ mechanism could inspire new therapeutic approaches.
