Induced epileptic seizures in larval zebrafish reveal a synaptic modulation associated with the post-ictal state.

Epilepsy patients suffer from spontaneous and recurrent seizures. In some cases, after seizures, a transient post-ictal state associated with cognitive deficits develops. Moreover, seizure-induced alterations in brain structure and function may give rise to neurological comorbidities associated with epilepsy. Nevertheless, the mechanisms underlying neurological comorbidities in epilepsy broadly and the post-ictal state specifically are not well understood. Here we used a well-established model of acutely induced seizures in larval zebrafish to reveal how seizures modulate a neural circuit implementing a specific sensorimotor transformation, the escape response. Using in vivo calcium imaging, we found that the responsivity of Mauthner cells, hindbrain command-like neurons that normally evoke fast and strong escape responses, to startling stimuli was reduced following seizures. Moreover, we observed a global reduction in post-seizure responsivity of neurons to the stimuli and in spontaneous neural activity. To identify structural correlates of these changes, we used expansion microscopy to characterize synaptic inputs to the Mauthner cells. Using this approach, we discovered that seizures increased the density of receptors in glycinergic inhibitory synapses onto these cells, expected to increase synaptic strength. This enhancement may compensate for the lack of GABAergic inhibition during the seizure. In addition, inducing the disassembly of glycinergic synapses by post-seizure strychnine treatment, reversed the effect of reduced neural responsivity. Put together, these data show that, at both the synaptic and circuit levels, inhibitory drive is strengthened after seizure termination, giving rise to a post-ictal state similar to that defined in humans. Consequently, sensory sensitivity is reduced, and post-seizure behavioural deficits are expected. These results reveal a potential target for pharmacological interventions that may mitigate neurological deficits in epilepsy when the seizures themselves cannot be prevented.