DISC-1 a genetic Model of Schizophrenia - Annissa DeSilva


  Schizophrenia has a heritability of about 80%, and numerous of candidate genes have been identified as “risk” genes of schizophrenia. Ayan et al, selectively expressed mutated human DISC-1 (hDISC-1) in mice during embryonic development, postnatally, or during both embryonic development and postnatally. In humans DSIC-1 encodes for a synaptic protein and is crucial for neuronal development in both pre and post-natal development, there is also evidence to suggest that those with mutated DSIC-1 are at higher risk to develop schizophrenia. What I found the most interesting about this paper is the separation of behavioral tests by gender based on the difference of schizophrenia symptomology seen between males and females (something that we have not seen in any of the previous models presented). Ayan et al found that female mice with the hDISC-1 mutation in the pre+post group had decreased mobility in the TST and the post hDISC-1 group had significantly more time immobile while the males had no significant effects between groups. This suggests that the during certain timepoints of expression hDISC-1 can produce depressive behavior in female mice. This is very interesting because in those with schizophrenia, females present with more mood disturbances and depressive symptoms versus males. Males with schizophrenia typically have more intense negative symptoms, thus I thought it was impressive that the male mice in the pre+post and the post group had significantly less social interaction and significantly more aggressive attacks. There is no mention on if this was performed on the female mice, as the paper only discusses the results of the male mice social integration, but it would be interesting to note if they found an effect of hDISC-1 mutation in females. I think this delineation between the effects on males and females contributes significantly to the validity of this model of schizophrenia, especially considering that the differences seen in this model mirror difference in the symptomology seen in clinical populations. The behavioral data nicely couples well with their finding that male mice had decreased levels of DA in the frontal cortex of all mutated hDISC-1 transgenic mice but only post DISC-1 female mice had decreased DA in the hippocampus suggesting hDISC-1 may affect brain development differently between males and females during differing periods of development. My immediate thought about this is related to sex hormones and their concentrations during brain development, how this could lead to the proteins encoded by DISC-1 to have differential effects by sex. However, it is still confusing that there were no gender differences seen in brain morphology. That being said, usually in humans in addition to the difference’s schizophrenic symptomology, females have a much later age of onset then males (males average age onset is 21-25 and females is between 25-30 or after 45). An interesting follow up to this experiment would be to see if the behavioral and histological effects of the DISC-1 mutation are emphasized or the results are altered if the female mice were tested in a later more adult stage of their life vs the males and analyze if the differences in the results are significantly effected by gender.

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