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Gamma protocadherins are required for synaptic development in the spinal cord
Joshua A Weiner1, Xiaozhong Wang, Juan Carlos Tapia
1Department of Anatomy and Neurobiology, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Summary
Protocadherins (Pcdhs) are crucial for synaptic development. Gamma-Pcdh loss in mice reduces spinal cord synapses, causing neurological defects, even when neuron loss is prevented.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fifty-eight cadherin-related protocadherin (Pcdh) genes are clustered on mouse chromosome 18.
- Pcdhs are implicated in specifying synaptic connectivity due to their abundance at synapses and cadherin superfamily functions.
- Previous studies showed Pcdh-gamma cluster deletion resulted in reduced spinal cord synapses and immobility, complicated by interneuron apoptosis.
Purpose of the Study:
- To investigate the direct role of Pcdh-gamma genes in synaptic development and function.
- To circumvent apoptosis and neurodegeneration in Pcdh-gamma mutant mice to isolate synaptic defects.
Main Methods:
- Generated Pcdh-gamma mutant mice lacking the proapoptotic protein Bax to prevent neurodegeneration.
- Created a hypomorphic Pcdh-gamma allele with minimal apoptosis.
- Analyzed synaptic density, neurological function, and cultured neuron synaptic function in these modified mutants.
Main Results:
- Both methods preserved spinal interneurons but revealed dramatically decreased spinal cord synapses.
- Mutant mice exhibited profound neurological defects.
- Synaptic function was compromised in neurons cultured from hypomorphic mutants.
Conclusions:
- Gamma-protocadherins play a direct role in synaptic development.
- These findings establish crucial genetic tools for further research into gamma-Pcdh function in synaptic specificity.
- The study confirms the importance of Pcdh-gamma in establishing proper neural circuitry and function.