Research Article

Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder

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Science  16 Apr 2021:
Vol. 372, Issue 6539, eaaz3893
DOI: 10.1126/science.aaz3893

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More is not always better

Mutations in X-linked genes usually affect male individuals more than females, but the opposite characterizes the Protocadherin-19 gene (PCDH19) on the X chromosome. Mutations in the PCDH19 cell-adhesion molecule cause cognitive impairment, affecting females more than males. Hoshina et al. studied mice with PCDH19 mutations, showing that a mismatch between PCDH19 and another cell-adhesion molecule causes trouble when mossy fibers of the brain are forming synapses (see the Perspective by Shohayeb and Cooper). In the heterozygous setting, mutant PCDG19 sequesters the partner cell-adhesion molecule into dysfunctional complexes. In the hemizygous setting, as in males, enough of that partner cell-adhesion molecule roams free to make functional interactions.

Science, this issue p. eaaz3893; see also p. 235

Structured Abstract


Mutations of the X-linked Protocadherin-19 (PCDH19) gene cause PCDH19 disorder with epilepsy. PCDH19 disorder is often associated with cognitive impairment and intellectual disabilities. Typically, X-linked disorders exhibit more severe phenotypes in males because of X-linked recessive inheritance. By contrast, symptoms of PCDH19 disorder manifest in heterozygous females, whereas hemizygous males are largely asymptomatic. Why this unusual presentation occurs is not known. PCDH19 encodes a single transmembrane protein that mediates cell-cell adhesion by homophilic binding through extracellular cadherin domains. A majority of PCDH19 mutations found in PCDH19 disorder alter sites in the extracellular domain of the PCDH19 protein, suggesting that the mutations may affect PCDH19 homophilic interactions and, as a result, cell-cell adhesion. We examined the precise roles of PCDH19 in the brain and the molecular, synaptic, and circuit bases of female-specific disease phenotypes.


PCDH19 disorder manifests in heterozygous females but not in hemizygous males. Because heterozygous females have a mixture of cells that express either the wild-type (WT) or mutant form of PCDH19, due to random X-inactivation, the mosaic expression of PCDH19 is proposed to cause pathogenic symptoms. To understand the roles of PCDH19 in the brain and the basis of female-specific disease phenotypes, we generated an animal model of PCDH19 disorder (Pcdh19 mutant mice). Because PCDH19 protein is highly expressed at hippocampal mossy fiber synapses, we examined the role of PCDH19 in mossy fiber synaptic development, function, and relevant cognitive behaviors. We then investigated the molecular bases of the female heterozygote–specific defects in Pcdh19 mutant mice. For this, we focused on the potential interaction between PCDH19 and N-cadherin (Ncad), another cell adhesion molecule localized at synapses. PCDH19 has been proposed to form a cis-complex with Ncad, which may mask the homophilic binding ability of Ncad. If the PCDH19 expression is mosaic (Pcdh19HET♀), the PCDH19-Ncad cis-complex could not mediate intercellular signals between PCDH19-positive and -negative cells. This PCDH19-Ncad mismatch would result in reduced downstream intracellular signals and cellular defects. We tested this possibility at mossy fiber synapses.


We found that Pcdh19HET♀ but not Pcdh19HEMI♂ mice show defects in mossy fiber presynaptic development, without changes in mossy fiber targeting, dendritic spine development, or postsynaptic development. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show decreased neurotransmitter release probability, impaired mossy fiber long-term potentiation (LTP), and deficits in mossy fiber–dependent cognitive function (pattern completion and separation). Furthermore, we found that PCDH19 appears to interact with Ncad at mossy fiber synapses. In Pcdh19HET♀ conditions, mismatch between PCDH19 and Ncad impairs Ncad-dependent β-catenin signaling and mossy fiber presynaptic development. Overexpression of Ncad in Pcdh19HET♀ mice restored not only β-catenin clustering in the mossy fiber synapses but also synaptic function, indicating that impaired Ncad function underlies the phenotype observed in Pcdh19HET♀ mice in vivo.


Pcdh19HET♀ and not Pcdh19HEMI♂ mice show mossy fiber presynaptic dysfunction and cognitive impairments, mimicking the female-specific manifestation of PCDH19 disorder. In Pcdh19HET♀ mice, mismatched interactions between two cell-adhesion molecules, PCDH19 and Ncad, impair Ncad-dependent signaling and, subsequently, presynaptic development. Pcdh19WT and Pcdh19HEMI♂ are spared because they have matched PCDH19 or Ncad interactions. This study not only uncovers distinctive female-specific disease mechanisms but also suggests possible strategies to treat the disorder on the basis of these molecular interactions.

PCDH19-Ncad mismatch underlies female-specific PCDH19 disorder.

At Pcdh19WT synapses, PCDH19-Ncad cis-complex mediates trans-synaptic signaling through PCDH19 homophilic matching and organizes presynaptic terminals. At Pcdh19HEMI♂ synapses, unmasked Ncad can mediate trans-synaptic signaling through Ncad homophilic matching. However, at Pcdh19HET♀ synapses between PCDH19-positive and PCDH19-negative neurons, PCDH19-Ncad cis-complex cannot trans-synaptically bind Ncad because of mismatching, leading to impaired presynaptic development, LTP, and cognition.


Protocadherin-19 (PCDH19) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females (PCDH19HET♀) but not hemizygous males (PCDH19HEMI♂); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET♀ but not Pcdh19HEMI♂ 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 Pcdh19HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin–dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.

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