Female-specific synaptic dysfunction and cognitive impairment in a mouse model of disorder.

() mutations cause early-onset seizures and cognitive impairment. The gene is on the X-chromosome. Unlike most X-linked disorders, mutations affect heterozygous females ( ) but not hemizygous males ( ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. but not mice show impaired mossy fiber synaptic structure and physiology. Consistently, but not mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific disorder phenotype.