Two distinct neural mouse models of schizophrenia- Sierra Smith

Moore et al and Kellendonk et al investigated the neural effects of altering two distinct hypotheses for the origin of schizophrenia symptoms in humans: increased amounts of the dopamine signaling in the striatum compared to asymptomatic conditions and gray matter reductions throughout the cortex and thalamus without affecting the actual neuronal cell count. These groups produced differential results based on whether they reversibly overexpressed D2Rs in the striatum via a transgenic mouse line (Kellendonk) or used MAM, a methylating agent, to stunt embryonic brain development via administration to the pregnant dam at either the litter’s embryonic day 15 or 17 (Moore).

Both groups’ measures of assessing schizophrenic symptoms in mice were quite interesting, I found, as I could not previously imagine how a research group might go about quantifying schizophrenia without being able to listen to the thought patterns of the mice. Methods included open field testing to assess overall locomotion, elevated plus maze to assess anxiety behavior, prepulse inhibition to measure startle response and sensorimotor gating, DNMTS maze testing to assess working memory, behavioral flexibility, and general cognitive deficit (Kellendonk), or simply open field testing, and prepulse inhibition (Moore). The Moore et al group was much more focused on the actual cellular and organizational phenotypes in the cortex and thalamus whereas the Kellendonk group examined far more different aspects of behavior in order to build a bigger picture of the functionality of the dopamine signaling when D2R receptors were overexpressed.

              In the end, Kellendonk et al report that their D2R overexpressing mice have reduced working memory abilities as well as behavioral flexibility that could not be overcome even when the excess D2R receptors were mitigated, but showed no impact on overall locomotion, anxiety behaviors, and sensorimotor gating.  Moore et al’s model, however, did yield defects in sensorimotor gating as well as overall symptoms of frontal corticostriatal signaling including ataxia, especially when MAM was administered at E15. These two very different models of schizophrenia both can be related to known correlates of schizophrenic symptoms in humans, but I wonder what proportion of humans either show decreased cortical and thalamic grey matter vs increased domapine signaling in the striatum compared to a combination of both. I’d be very interested to see more mild combinations of both of these models tested in mice in order to build an even bigger picture of the spectrum of schizophrenia seen in humans.