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Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse
D C Ung1,2, G Iacono3, H Méziane4
1University François-Rabelais, UMR Imaging and Brain, Tours, France.
Molecular Psychiatry
|April 19, 2017
Summary
Mutations in the PTCHD1 gene are linked to neurodevelopmental disorders. PTCHD1 deficiency in mice impairs excitatory synapses, leading to cognitive and motor deficits, supporting its role in brain development.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Synapse development and neuronal activity are crucial for cognitive function and are disrupted in neurodevelopmental disorders like autism spectrum disorder (ASD) and intellectual disability (ID).
- Deleterious mutations in the PTCHD1 gene are associated with X-linked ID and/or ASD in male patients.
- The cellular functions of PTCHD1 in brain development are not well understood, despite its structural similarity to the Patched (PTCH1) receptor.
Purpose of the Study:
- To investigate the cellular mechanisms and pathways involving PTCHD1 in the developing brain.
- To determine the role of PTCHD1 in synaptic structure, gene expression, and neuronal activity.
- To elucidate the contribution of PTCHD1 deficiency to neurodevelopmental disorders.
Main Methods:
- Investigated PTCHD1's interaction with postsynaptic proteins using its C-terminal PDZ-binding motif.
- Assessed PTCHD1's ability to rescue the sonic hedgehog (SHH) pathway in PTCH1-depleted cells.
- Analyzed synaptic gene expression, including immediate-early genes (Egr1, Npas4), in Ptchd1-deficient male mice (Ptchd1-/y).
- Examined hippocampal excitatory synaptic structure and neuronal activity in Ptchd1-/y mice.
Main Results:
- PTCHD1 binds to postsynaptic proteins PSD95 and SAP102 via its C-terminal PDZ-binding motif.
- PTCHD1 does not rescue the canonical SHH pathway in PTCH1-depleted cells, indicating distinct signaling roles.
- Ptchd1 deficiency in mice led to global changes in synaptic gene expression, including Egr1 and Npas4.
- Impaired excitatory synaptic structure and neuronal activity were observed in the hippocampus of Ptchd1-/y mice.
- Ptchd1 deficiency resulted in cognitive dysfunction, motor disabilities, and hyperactivity.
Conclusions:
- PTCHD1 functions in distinct cellular signaling pathways separate from PTCH1 and the SHH pathway.
- PTCHD1 plays a critical role in regulating synaptic gene expression, structure, and neuronal activity.
- PTCHD1 deficiency causes excitatory synaptic dysfunction, leading to a neurodevelopmental disorder with cognitive and motor impairments.
