Moore and Kellendonk et al.

Moore et al. (2006) convinced me that the MAM-E17 rat is a good model for schizophrenia.  It was smart of them to compare histopathology and behavior of MAM-E17 rats to MAM-E15 rats because those two stages of embryonic development mark a major change in neuron proliferation.  I did not understand why they stopped comparing E17 and E15 rats during most of the experiments.  They injected MAM, a neurotoxin that induces phenotypes analogous to those in schizophrenia, into pregnant mice at E15 and E17.  Morphological changes were similar to those in human schizophrenia brains.  MAM caused a reduction in sizes of cortical and subcortical regions in E15 brains, but E17 brains only had a slight reduction in cortical size.  However, MAM reduced thickness of the hippocampus and thalamus in E17 rats.  With regards to behavior, MAM-E15 rats showed significantly greater levels of ataxia.  E17 rats expressed reduced pre-pulse inhibition, impaired spatial working memory, a deficit in reversal learning, and increased responsiveness to amphetamines.  The problem with this study is that they use a neurotoxin to induce schizophrenic phenotypes instead of trying to find an endogenous molecule or gene that causes it.

What I liked about the Kellendonk et al. (2006) paper is that it focused on one part of the brain, the striatum.  The authors increased the number of D2 receptors in the striatum to test how dopamine sensitivity affects cognition.  Overexpression of these receptors did not alter locomotor activity, sensorimotor gating, or anxiety.  However, this increase did cause deficits in working memory and behavioral flexibility, processes dependent on the pre-frontal cortex.  Kellendonk et al. (2006) showed that over-expression of D1 receptors in the striatum correlated with the decrease of D1 receptor activation in the frontal cortex of mice, which mimicks the neurocognitive deficits of schizophrenia.  In addition, reversal of D2 receptor overexpression by Dox did not reverse the cognitive deficits.

I think that the Moore et al. (2006) experiment confirmed that particular brain morphology is associated with schizophrenia.  However, Kellendonk et al. (2006) convinced me of a molecular mechanism by which schizophrenic symptoms can come about.