NRSC 4132 Blog

Psychiatric disease genes in humans are exceedingly difficult to study. The disease features and symptoms present can differ among individuals and may differ in severity. Polygenic inheritance and gene-environment interactions play a role in these diseases, making it difficult to decide how many genes contribute to the disease and whether a behavior should be attributed to genes or to environmental influences. For these reasons, using mouse genetics is beneficial; the environmental and genetic makeup can be controlled for. In order to be able to generalize the results to humans, the researchers in this study created transgenic mice that expressed the human orphan nuclear receptor 2E1 (NR2E1) to see how the gene affected the behavior of the mice. Abrahams et al. studied four types of mice: wild-type, transgenic (contains human NR2E1 gene), fierce (NR2E1 deletion), and rescue (NR2E1 replaced during adulthood). Without NR2E1, mice would demonstrate pathological violence, in addition to physical abnormalities. These NR2E1 null mice are referred to as "fierce." Additionally, the presence of a transgene spanning human NR2E1 can eliminate the brain and eye abnormalities and restore normal behavior to fierce mice, implicating possible treatments for psychiatric diseases that involve pathological behaviors.

Physical abnormalities were abundant in fierce mice, whereas transgenic and rescue mice were phenotypically indistinguishable from wild-type mice. Brain abnormalities in fierce mice included hypoplasia of the olfactory bulbs and anterior cortex, which was determined by an analysis of the surface areas of these regions. This damage left midbrain colliculi exposed. Additionally, the brain contained an abnormally small forebrain, abnormally shaped cingulum, poorly defined piriform cortex, smaller anterior commissure, abnormal cortical lamination, a reduction in striatal volume, an enlargement of corticostriatal fibers, and a thin external capsule of the corpus callosum. Eye abnormalities included radial asymmetry, mottling of the retinal pigment epithelium, and a reduction in retinal vessel number. It should be noted that rescue mice had a significantly reduced vessel number compared to wild-type and transgenic, though they were phenotypically normal by qualitative and quantitative analyses. Behaviorally, fierce mice were more spontaneous, more aggressive (to the point that they would attack or kill mates), and less social than the mice of the other three genotypes.

NR2E1 is transcribed in regions important for neurogenesis and it is thought that it suppresses the differentiation of neuronal stem cells. Since NR2E1 deletion produces physical abnormalities in the brain, it is thought that the available stem cells cannot form into the proper structures through neurogenesis. Although this explains the physical abnormalities, it remains unknown whether abnormal behavior results from improper brain development or from a deficiency in NR2E1 signaling. In humans, it is more likely that a subtle variation of NR2E1, rather than a gene deletion, is at work to produce behavioral abnormalities. For instance, NR2E1 may play a role in bipolar disorder, and only a small portion of the gene is disrupted. Abrahams et al also note that genes that interact with NR2E1 may be involved in psychiatric disease, so association studies should be done to examine other contributors to psychiatric diseases.

Ultimately, few transgenic rescue experiments have been done, although they are increasing in popularity. The few that have been done have prevented embryonic lethality using a human gene as a rescue, but have not improved abnormal behavior. This study was instrumental in demonstrating that rescue genes can correct abnormal behavior.

Source: http://www.jneurosci.org/content/25/27/6263.full.pdf+html?sid=44333731-d47a-48fc-80df-d59af7a07702