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PMID:27779093
| Citation |
Harrington, AJ, Raissi, A, Rajkovich, K, Berto, S, Kumar, J, Molinaro, G, Raduazzo, J, Guo, Y, Loerwald, K, Konopka, G, Huber, KM and Cowan, CW (2016) MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife 5 |
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| Abstract |
Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) - a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice. |
| Links |
PubMed PMC5094851 Online version:10.7554/eLife.20059 |
| Keywords |
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Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:1904891: positive regulation of excitatory synapse assembly |
ECO:0000315: |
P |
Figure 3 shows that in the absence of MEF2C, excitatory synapse density is decreased. |
complete | ||||
| GO:1905703: negative regulation of inhibitory synapse assembly |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Figure 3 shows that, in the absence of MEF2C, inhibitory synapse density increases. |
complete | ||||
| GO:0061003: positive regulation of dendritic spine morphogenesis |
ECO:0000315: |
P |
Figure 3 (F and G) shows that MEF2C mutation (MEF2C-VP16) and an MEF2C knockout decreases dendritic spine density. Knockout MEF2C cells supplemented with functional MEF2C-EN are able to restore and maintain dendritic spine density. |
complete | ||||
| GO:1902952: positive regulation of dendritic spine maintenance |
ECO:0000315: |
P |
Figure 3 (F and G) shows that MEF2C mutation (MEF2C-VP16) and an MEF2C knockout decreases dendritic spine density. Knockout MEF2C cells supplemented with functional MEF2C-EN are able to restore and maintain dendritic spine density. |
complete | ||||
| GO:0032229: negative regulation of synaptic transmission, GABAergic |
ECO:0000315: |
P |
Figure 3 (H and I) shows that MEF2C mutant (MEF2C-VP16) and MEF2C knockout mutants increase GABAergic synapse density. Knockout MEF2C mutants supplemented with functional MEF2C-EN were able to decrease GABAergic synapse density to wildtype levels. By decreasing GABAergic synapse numbers, MEF2C negatively regulates GABAergic synaptic transmission. |
complete | ||||
Notes
See also
References
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