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Baker-Gordon Syndrome-Associated Synaptotagmin-1 Mutations Reduce Synaptic Strength in Mouse Primary and
Pascal Fenske1, Hassan Hosseini1, Boris Bouazza-Arostegui1
1Charité - Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence, Institute of Neurophysiology, Berlin 10117, Germany.
Summary
Mutations in Synaptotagmin-1 (SYT1) cause Baker-Gordon syndrome. Overexpressing mutant SYT1 in human or mouse neurons showed a dominant-negative effect, impacting synaptic transmission and neurodevelopmental disorder pathology.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder linked to mutations in Synaptotagmin-1 (SYT1), a key calcium sensor for synaptic transmission.
- Understanding the molecular mechanisms of BAGOS requires studying SYT1 function in neuronal models.
Purpose of the Study:
- To compare the functional impact of BAGOS-associated SYT1 mutations in mouse and human neuron models.
- To investigate the rescue potential of SYT1 mutants in knockout models and their effects in wild-type neurons.
Main Methods:
- Generated and utilized SYT1 knockout (KO) mouse models.
- Created SYT1 KO human induced pluripotent stem cell (hiPSC)-derived neurons using CRISPR/Cas9 gene editing.
- Assessed synaptic transmission and neurotransmitter release efficacy in response to SYT1 variants.
Main Results:
- SYT1 KO in both mouse and human neurons impaired synchronous neurotransmitter release.
- BAGOS SYT1 mutants showed partial rescue of fast synaptic transmission in human KO neurons.
- Overexpression of BAGOS SYT1 mutants in wild-type neurons exhibited a dominant-negative effect on synaptic transmission.
Conclusions:
- Species-specific variations exist in the functional consequences of SYT1 mutations.
- Mutant SYT1 proteins can exert dominant-negative effects, contributing to neurodevelopmental disorder pathophysiology.
- Structure-function studies in relevant species-specific contexts are crucial for understanding neurological disorder mechanisms.
