2019 Biopsych Seminar Thursdays

Ayhan et al. and Burrows et al. wrote articles on differing approaches to modelling schizophrenia in mice. Ayhan and colleagues’ 2011 article focused on DISC1 and how it can be a risk factor for schizophrenia based on its effects during several stages of neurodevelopment. They cited the neurodevelopmental hypothesis, which states that both prenatal and early postnatal abnormalities can contribute to the development of schizophrenia and other mood disorders. They studied whether prenatal and/or postnatal expression of mutant DISC1 would give mice symptoms reminiscent of schizophrenia. Their four experimental groups all had a mutant hDISC1 gene; the different was when it was suppressed by Dox. Table 1 contained a summary of results, and there were a few observations that stuck out. All groups (aside from controls) had fewer PV cells and decreased levels of dopamine in the male frontal cortex. The Pre+Post group showed decreased social behavior and increased aggressive behavior, while t...

Ayhan et al. developed a transgenic mouse model with tet-off inducible expression of the mutant human DISC1 (hDISC1), a protein linked to neuronal and synaptic development and implicated in schizophrenia pathophysiology. Side note -- I wonder how much can be gleaned from the function of a human transgene in a mouse setting? Nonetheless, selective prenatal expression of the transgene led to reduced brain volume and increased spine density in pyramidal cortical neurons, paralleling previous findings of decreased neuronal proliferation with DISC1 knockdown that gives rise to smaller brain volumes in adult mice. Notably, postnatal expression alone led to larger lateral ventricles and decreased cortical volume, which is in line with the hypothesis that gradual postnatal changes drive ventricular pathology in schizophrenia. It’s interesting that prenatal and postnatal expression both independently influenced GABA-ergic interneuron development. I liked the authors’ interpretation that mutan...

This week we take a look at two articles form early 2006 focused on animal models of schizophrenia. Each of the articles develops and tests a distinct mouse model for schizophrenia. Importantly, both of these models are especially focused on the cognitive symptoms of schizophrenia, which other models do not present and which are not primarily targeted by current treatment in humans.  In the article by Moore and colleagues (2006), the model is achieved by disrupting embryonic development of paralimbic frontal and temporal cortices, while in the article by Kellendonk and colleagues (2006) the model is achieved by overexpressing D2 receptors in the striatum. Results in cognitive tasks are not unlike in the two models, which highlights the fact the schizophrenia might be better conceptualized as a heterogeneous disease in which different neurobiological substrates given origin to similar symptoms across individuals. This means that not one model might be truer to the human disord...

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 o...

            The papers this week both focused on animal models of schizophrenia, a rather uniquely challenging mental illness. Kellendork  et al.  investigated the link between overactive dopamine function and schizophrenia-like behaviors and changes in mice. Moore  et al.  took an extremely different approach by specifically targeting specific cortical development in rat embryos. Despite both papers’ similarity and the fact that they were published the same year, they have very different styles. I assume this was due to some combination of different journal expectations and differing backgrounds of the authors, but it was interesting to notice. Both papers found task deficits in working memory and behavioral flexibility, which are commonly found in human schizophrenia patients.             Kellendork  et al.  began with a dopamine hypothesis of schizophrenia, ...

Moore et al. focused on the existing hypothesis that schizophrenia is a result of abnormal brain development, particularly in frontal and limbic cortical circuits and dopaminergic inputs to the striatum. The current study used MAM to disrupt development of E15 and E17 mice, focusing on the effect on the morphology of paralimbic frontal/temporal cortices and medial dorsal/midline thalamic nuclei. Furthermore, corticostriatal circuit function was analyzed to extend research on cognitive deficits in MAM-E17 mice. MAM decreased brain weight and universal brain region size in both E15 and E17 groups, even though the MAM-E17 group showed no change in number of cells. MAM-E17 showed a more schizophrenic-like decrease in grey matter and an increase in density in the prefrontal/cingulate and insular/perirhinal zones. These neurons in the prefrontal cortex showed a more depolarized resting potential and spike threshold, and the average spike threshold was more depolarized. Behavioral abnormal...

That over-expression of D2 receptors in the striatum would cause cognitive deficits related to expression of receptors during the developmental time line, rather than consistent dopamine elevated release, is a fascinating point. I had always been interested in the comparative effects between either increasing concentration of a neurotransmitter or increasing the concentration of receptors for a neurotransmitter and leaving its basal concentration the same. On the one hand, you have more bioavailability to reach receptor targets, while on the other hand you have greater surface area distribution of receptors that can cause activation. One might assume that the results of these processes are the same, and yet the Kellendonk paper shows that there is indeed a difference between the two. Perhaps the very reason that classical antipsychotics, which are D2 receptor antagonists, display only moderate effectiveness, is because schizophrenics already have such a high distribution of dopamine ...