Female-specific synaptic dysfunction and cognitive impairment in a mouse model of <i>PCDH19</i> disorder.

Abstract

<i>Protocadherin-19</i> (<i>PCDH19</i>) mutations cause early-onset seizures and cognitive impairment. The <i>PCDH19</i> gene is on the X-chromosome. Unlike most X-linked disorders, <i>PCDH19</i> mutations affect heterozygous females (<i>PCDH19^HET♀</i> ) but not hemizygous males (<i>PCDH19^HEMI♂</i> ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. <i>Pcdh19^HET♀</i> but not <i>Pcdh19^HEMI♂</i> mice show impaired mossy fiber synaptic structure and physiology. Consistently, <i>Pcdh19^HET♀</i> but not <i>Pcdh19^HEMI♂</i> 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 <i>Pcdh19^HET♀</i> conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues <i>Pcdh19^HET♀</i> phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific <i>PCDH19</i> disorder phenotype.