This week’s pair of papers focuses on schizophrenia and the generation of schizophrenic phenotypes in rodents using transgenic mice either lacking metabotropic glutamate receptor 5 or with expression of mutant Disrupted-In-Schizophrenia 1, quite possibly the least imaginative name for a gene in all of genetics. Ayhan et al 2011 focused on the latter, expressing a mutant form of human DISC either prenatally, postnatally, both, or neither in mice. From this, the team found that expressing the gene both pre- and post-natally induced depressive symptoms, social aggression, and responsiveness to stimulants, while prenatal expression decreased brain volume and postnatal expression produced depressive symptoms, enlarged ventricles, and decreased dopamine in the hippocampus. While the post- and pre-natal expression group were found to have the greatest effect, this may have been from an overexpression of the mutant gene that had broader downstream effects than might be accounted for in a schizophrenic model. IF this is the case, then as far as schizophrenic models go, the postnatal exposure group seems to be the most accurate in replicating human schizophrenia due to its effect on dopamine, ventricle size, and general social/behavioral effects, though there aren’t any effects that aren’t also in the both group.
An interesting tie that binds the Ayhan paper with the Burrows et al 2015 paper is the effects of MK-801, an NMDA antagonist, on the “schizophrenic” mice at hand. Ayhan et al found that MK-801 increased motor activity in the pre- and post- group, while Burrows likewise found that MK-801 increased activity in mGlu5 knockout mice and was even more effective in mGlu5 KO mice that had received enriched environments, though it also had a significant effect on PPI even at low doses. Together, both studies seem to implicate both mGlu5 and DISC1 in a relationship with NMDA and the subsequent effects of glutamate, NMDA, and NMDAR modulation in a schizophrenic model. As such, a future paper could combine the findings, perhaps finding the effects of both modulated mGlu5 and DISC1 expression on producing schizophrenic symptoms, or perhaps simply the effects of modulated NMDAR in producing such a model. As well, because of NMDAR’s implication in neural plasticity and expression patterns, perhaps NMDAR could be the key to the delayed expression of symptomology found in human schizophrenia.