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Published on: May 12, 2015
Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder
Naosuke Hoshina1, Erin M Johnson-Venkatesh1, Miyuki Hoshina1
1Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Insights
Protocadherin-19 (PCDH19) mutations cause female-specific neurological disorders. PCDH19 protein interacts with N-cadherin at synapses, and its absence impairs synaptic function and cognition in female mice.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Protocadherin-19 (PCDH19) mutations are linked to early-onset seizures and cognitive impairment.
- PCDH19 gene is X-linked, but mutations uniquely affect heterozygous females, not hemizygous males, a phenomenon requiring explanation.
Purpose of the Study:
- To investigate the molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.
- To elucidate the role of PCDH19 in synaptic function and its interaction with other cell adhesion molecules.
Main Methods:
- Utilized mouse models (Pcdh19 knockout) to study synaptic structure and physiology.
- Assessed cognitive functions related to hippocampal mossy fiber synaptic activity.
- Investigated protein-protein interactions between PCDH19 and N-cadherin at synapses.
Main Results:
- PCDH19 is enriched at hippocampal mossy fiber synapses.
- Pcdh19 knockout mice exhibit impaired mossy fiber synapse structure and physiology.
- Pcdh19 knockout mice show deficits in pattern completion and separation, indicating impaired hippocampal function.
- PCDH19 interacts with N-cadherin; a mismatch in Pcdh19 conditions disrupts N-cadherin signaling and synapse development.
- N-cadherin overexpression rescued the Pcdh19 phenotypes in mice.
Conclusions:
- PCDH19 is crucial for normal mossy fiber synapse development and function.
- The interaction between PCDH19 and N-cadherin at synapses is vital for preventing the disorder phenotype.
- These findings reveal the molecular basis for female-specific PCDH19-related neurological disorders.
Abstract:
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 (PCDH19 ) but not hemizygous males (PCDH19 ); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19 but not Pcdh19 mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19 but not Pcdh19 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 Pcdh19 conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin-dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19 phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.
