Understanding the potential pathogenetic or pathophysiological
significance of any brain alteration associated with schizophrenia requires
the determination of whether the observed abnormality represents the
direct result of a potential causal factor, a deleterious consequence
of more primary events, or a compensatory response. Because direct studies
of the diseased brain are usually restricted to correlational observations,
discriminating between "cause, consequence and compensation"
requires studies of cause and effect in more tractable systems. Hence,
in this fourth line of investigation, we utilize "proof of principle"
approaches that involve experimental manipulations in both rodent and
primate model systems. For example, Program member Dr. Takanori Hashimoto
uses genetic manipulations in mice to determine whether expression changes
in certain trophic factors may be the proximal cause of the observed
alterations in certain populations of DLPFC neurons in schizophrenia
(Figure 1).
|
| Figure 1. Changes in gene expression in the prefrontal
cortex of the TrkB hypomorphic mice are similar to those in subjects with
schizophrenia. Representative pseudocolored autoradiograms illustrate
the decreased expression of TrkB, GAD67 and PV mRNAs in mice heterozygous
or homozygous for the fBZ locus. The mean (SD) expression level of each
transcript is reduced in a gene-dose dependent fashion. Within each graph,
bars not sharing the same letter are significantly different (p<.05).
(Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience 6:312-324, 2005.) |
