Synaptic Profiling of Excitatory Inputs onto Parvalbumin Positive Interneurons in PCDH19-related Epilepsy

Parvalbumin-positive interneurons (PVIs) play a fundamental role in excitatory/inhibitory balance regulation. PVIs are fast-spiking, highly interconnected GABAergic neurons that act as local gain controllers, synchronizing network activity and support gamma oscillations involved in higher-order cognition. Dysfunctions in this neuronal subtype have been implicated in several neurodevelopmental and neuropsychiatric conditions; of our interest is their involvement in the pathogenesis of PCDH19-related epilepsy1. In this study, we are exploiting a conditional knockout mouse model with PCDH19 deletion restricted to PVIs and visualized by TdTomato expression. This model was demonstrated to replicate key behavioral and electrophysiological alterations of the disease. Ultrastructural analysis showed that PCDH19 loss alters both pre- and postsynaptic compartments of excitatory and inhibitory synapses in the prefrontal cortex. Moreover, to delineate the dendritic complexity of PVIs and their specific synaptic inputs profiling, we applied a volume correlative light and electron microscopy pipeline. This method allows detailed and cell-type specific analysis, revealing links between altered morphological connectivity and functional abnormalities in this neuronal population.