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9 Cards in this Set
- Front
- Back
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1) So what was the conclusion that they found in the C4 expression experiment? s8 |
1) If have C4A long form, 1.3 x higher chance of having schizo. β value was calculated from C4A RNA expression; which showed the correlation. Each given C4 structure should exhibit same characteristic risk regardless of what MHC haplotype; C4A the highest chance. |
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1) What is the C4 system and what does it do in the brain and where was it found? s13 |
1) Part of the immune complement system in the body; same protein has different function in the brain.
-> In the brain, implicated in elimination of synpases (Cortical thinning). Immunochemistry on sections of prefrontal and hippocampus showed C4 cells in grey and white matter. Greatest number in hippocampus. -> Co-staining with cell-type-specific markers revealed C4 in subsets of NeuN+ (marker for neurons) neurons and a subset of astrocytes |
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1) What did they observe through immunohistochemistry and what technology did they use? s14 |
1) Most staining observed was punctuate. They used High resolution structured illumination microscopy (SIM) for imaging of tissue in the hippocampal formation, showed localization of C4 in both presynapatic terminal markers VGLUT1/2 (glutamate transporter markers) and the postsynaptic marker PSD-95 (post synaptic density protein). |
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1) What did the confocal images of human cortical neurons show? s15 |
1) Showed localization of C4, MAP2, neurofilament along neuronal processes. Stained for C4, presynaptic marker synaptotagmin, and postsynaptic PSD-95. So again it showed C4 presence at the C4. |
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1) So what implications do the findings have on the current schizophrenia models? s17 |
1) -> association of increased C4 with schizophrenia and the presence of C4 at synapses; and implication of other complement proteins e.g. C3 in synapse elimination -> Some reports have showed decreased synapse number in schizo. -> Suggesting that C4 might work with other C proteins |
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1) Describe the complement model they used to test hypothesis in mice. Describe the C4/C3 protein roles in the mice. s18 |
1) -> Mouse genome has C4 protein that shares features of both C4A and C4B. C4 activates C3, allowing C3 opsonization. -> In mouse brain, C3 targets subsets of synapses and is required for synapse elimination by microglia, the principal CNS cells expressing receptors for complement. |
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1) What did they observe when they knocked out C4? s19 |
1) C3 immunostaining in the dLGN was reduced compared to WT.
Fewer synaptic inputs from C3 positive. Implicates role for C4 in complement mediated synaptic formation/pruning. |
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1) So what does the results indicate? s21 |
1) -> C4 expressed by neurons, localized to dendrites, axons and synapses, and may also be secreted (co-localized, pre and post with expression in punctae). So if C4 KO reduces C3; overexpression could have caused a lot of synaptic pruning. |
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1) How do the findings fit in with the human model and the schizophrenia mechanism? s22 |
1) -> In humans, adolescence and early adulthood bring extensive elimination of synapses in distribution association regions of cerebral cortex, such as prefrontal. -> Synpase elimination normally goes up to 30s. This late maturation phase corresponds to the period of schizophrenia becomes clinically apparent. -> C4A more readily forms amide bonds with proteins, while C4B favours binding to carbohydrate surfaces. This could mean that C4A and C4B differ in affinity for an unknown binding site at synapses. -> increased risk associating with higher C4A expression. |
