Moore et al vs Kellendonk et al
Seminar in BioPsych
Schizophrenia is a notoriously difficult mental illness to model, particularly because it it epigenetic and polygenic. Moore et al sought to create a reliable model for this disease in the rodent by carefully administering methylazoxymethanol acetate (MAM) at different stages in embryonic development. It had previously been shown that MAM administration on E15 led to development of a considerably smaller head; however, that is not typical of schizophrenic patients. The goal is to create a model that exhibits the anatomical, functional, and behavioral deficits of typical schizophrenic patients, and so Moore et al thought to try administering MAM two days later, on E17, when most proliferation of neurons has peaked in the cortex, so development would not be affected as strongly.
Fortunately, MAM-E17 mice did not exhibit the microcephaly that MAM-E15 mice did; their heads were similar in size to control mice. Moreover, brain region morphologies were similar to controls, aside from a slight reduction in cortical size. Very interestingly, they noticed that overall neuronal count was not affected; however, a reduction in density of neurons in one part of the brain was coupled with an increased density of neurons in another — to maintain the overall neuronal count. They tested a bunch of other measures to compare these mice to controls: electrophysiological recordings which showed that resting potentials in MAM-E17 mice were more depolarized than controls, but, interestingly, those same neurons were not more easily excited; behavioral assays which showed that experimental mice did not show gross motor abnormality, but did show a deficit in prepulse inhibition; pharmacological experiments which showed that MAM-E17 mice were more sensitive to increased schizophrenic stereotypies after PCP administration; and lastly, another pharmacological experiment which manifested a dichotomous responsiveness to amphetamine in prepubertal versus adult mice.
I’ve thought about what it would take to create a reliable model for a disease, or even just to create a transgenic mouse that behaves “normally” and I would imagine that it would require a plethora of intricate experiments with potentially shaky interpretations, because what does it really mean for a mouse to have schizophrenia — the florid symptoms can never be verified. Thus, I’m not sure I’m content with this series of experiments — not because of unruly data representation, but because I’m not sure how well a mouse model can truly represent the animal correlate of a schizophrenic patient. (It’s also interesting to note that it isn’t known how MAM methylation is preferentially targeted in cortical neurons.) Maybe there’s a more modest approach that may be more telling.
That brings us to Kellendonk et al, which was published just a month after Moore et al, and both papers came out of Columbia University. These experimenters thought: D2 receptor dysfunction has been implicated in schizophrenia in humans — specifically in the striatum —, and this dysfunction has a behavioral effect on working memory, which is known to be carried out largely by the prefrontal cortex (PFC). Thus, they thought, does overexpression of D2Rs in the striatum lead to cognitive deficits, and then, downstream, how is the PFC affected?
They adopted a tet-tag strategy to overexpress D2Rs in the striatum of transgenic mice. These mice were kept off dox to maintain overexpression; however, some of the experiments showed that introducing dox to return D2R expression back to normal did not reduce behavioral symptomatology — in fact, they may have exacerbated it. The first few experiments served to show that this mouse does indeed show dopamine activity level changes that parallel those of schizophrenic patients, and the next few experiments showed that locomotion, sensorimotor gating, and generalized anxiety levels were not vastly different from control animals. Then, the big experiment showed that these mice indeed showed a deficit in working memory, which is what they were hoping. So their next question was: what’s going on downstream of the striatum to lead to this behavioral deficit? They showed that lesioning the PFC led to a similar decline in ability to complete the working memory task, and this paralleled the decline in D2R transgenic mice. So the PFC is probably somehow involved in this deficit, but how? Well, DA innervation to the PFC seemed normal, as evidenced by density of TH-positive axon terminals in the PFC of experimental vs control mice. But, the levels of dopamine compared to its metabolites showed that dopamine was not getting biotransformed normally. Furthermore, administration of a selective agonist of excitatory DA receptors (D1R and D5R) showed a much stronger cfos activation in the PFC, but when the transgene was turned off, this cfos activation was much weaker! So overexpression of D2R probably has something to do with this downstream effect.
This approach to finding a neurobiological correlate of schizophrenia was much more modest and, in my opinion, more successful, than that of Moore et al. Instead of administering a drug whose drug action is not entirely understood and attempting to run after all the possible relations to human schizophrenia that it may have, Kellendonk et al took a much more targeted and controlled approach, by looking at DA receptor modulation, particularly because many schizophrenia treatments are based on DA modulation. I don’t know very much (anything) about schizophrenia, but I agree much more with the approach of Kellendonk et al than with that of Moore et al.