Circuit mechanisms underlying chronic epilepsy in a mouse model of focal cortical malformation

Abstract

HighlightsO_LIEctopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons is a key component of the hyperexcitable circuitry C_LIO_LIDisrupted E/I balance was located far away from cortical malformations C_LIO_LIDendritic inhibition from somatostatin interneurons play a key role in epileptogenesis C_LIO_LIClosed-loop optogenetic stimulation to activate remainder somatostatin interneurons irreversibly stops the spontaneous spike-wave discharges in vivo. C_LI In BriefYang et al. report abnormal synaptic reorganization in an epileptogenesis zone in a mouse model of cortical malformation. The authors further demonstrate that spontaneous spike-wave discharges can be curbed by selectively activating somatostatin interneurons using close-loop fiber optogenetic stimulation to a small cortical region away from the microgyrus. SummaryHow aberrant neural circuits contribute to chronic epilepsy remains unclear. Using a mouse model of focal cortical malformation with spontaneous seizures, we dissected the circuit mechanisms underlying epileptogenesis. Spontaneous and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (> 1mm) freeze-lesion induced microgyrus, instead of a region near it. ChR2-assisted circuit mapping revealed ectopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons as a key component of the hyperexcitable circuitry. This disrupted balance between excitation and inhibition was prominent in the cortical region distal to the microgyrus. Consistently, the synapses of both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were maladaptive in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate highly site- and cell-type specific synaptic reorganization underlying chronic cortical epilepsy and provide insights into potential treatment strategies for this devastating neurological disorder.