Investigating the role of parvalbumin positive interneurons in PCDH19-related Developmental and epileptic encephalopathy-9 (DEE9)

Developmental and Epileptic Encephalopathy 9 (DEE9) is a neurodevelopmental disorder characterized by epilepsy, cognitive impairment, and behavioral and psychiatric defects. DEE9 is caused by mutations in the PCDH19 gene that encodes for protocadherin-19 (PCDH19), a protein that promotes proper adhesion between neurons in the brain. The mechanism linking the mutations to the disorder is still unknown. PCDH19 is present in excitatory and inhibitory neurons and at their synapses where it plays an important role in modulating neurotransmission.

If we remove PCDH19 in a specific type of inhibitory neurons, called parvalbumin neurons (PVIs) and known to be involved in ASD and epilepsy, in the brain of a mouse, we see an increase in its cortical activity (the electrical activity that, in our brains, we can measure with ECG). Furthermore, the mouse also shows defects in social interactions and displays an autistic-like behavior.  These striking observations suggest a correlation between the lack of PCDH19 in parvalbumin neurons and the appearance of hallmarks of the human disease in the mouse. Therefore, understanding which are the consequences of the absence of PCDH19 in parvalbumin neurons on the structure and function of neurons and synapses in the prefrontal cortex is very important. In fact, this brain region is particularly rich in parvalbumin neurons. By understanding the impact of its absence in brain function, we might open new avenues for the development of promising drugs whose activity will have an impact on the severity of DEE9 in children.