Hippocampal Chandelier Cells Modulate Seizure Susceptibility and Severity

Abstract The axon initial segment (AIS), serving as the site for initiating action potentials (APs), is a key target for efficient regulation of neuronal activity. In mammals, chandelier cells (ChCs) represent a distinct subtype of GABAergic interneurons that selectively target the AIS of projection neurons (PNs). This strategic property endows them with the potential to effectively control the firing of PNs. They respond to diverse physiological stimuli and undergo homeostatic plasticity during network hyperactivity. However, their response in pathological states, such as epileptic seizures, remains unclear. In this study, we observed an increase in the ChC Ca 2+ signal following the rise of ictal discharges. Blocking ChC synaptic transmission in the hippocampal CA1 region placed animals in a subthreshold status to develop seizures and heightens susceptibility and severity to kainic acid (KA)‐induced epilepsy. Furthermore, bidirectional chemogenetic modulation of ChCs altered seizure susceptibility, supporting the hypothesis that ChCs safeguard the network activity. Notably, boosting ChC activity during the chronic phase mitigated spontaneous seizures. Additionally, intensified ChC‐AIS innervation is observed following status epilepticus (SE), suggesting a homeostatic protective role of ChCs. The findings revealed an active anti‐ictogenic role of ChCs during seizures, highlighting their protective function in pathological conditions.