Genetic Based Models

Generated. Although not straightforward in polygenic diseases such as schizophrenia, transgenic animals are being created to study possible candidate susceptibility genes. This approach can involve making knockouts (or knockdowns) of genes based on linkage analysis (Gainetdinov et al., 2001; Kilts, 2001). For instance, three separate genetic strains have been generated that delete the mouse equivalent (on chromosome 16) of the human 22q11 deletion that produces VCFS, which closely resembles the schizophrenia phenotype. These mice show some cardiovascular morphology and behavior that resembles their human counterpart; however, there is tremendous variability observed in these animal models.

Models can also be generated based on their function. For example, knockouts have been generated for candidate molecules such as N-CAM. These mice have abnormal neuronal migration, altered cytoarchitecture in several brain regions, enlarged ventricles, and deficits in PPI. Knockouts have also been generated for dopamine-related molecules such as dopamine receptors, the dopamine transporter, and catechol- O -methyltransferase (COMT), the major enzyme involved in the extraneuronal degradation of dopamine. These mice are hyperactive, stereotypic, and have reproduced some of the cognitive and gating impairments seen in patients with schizophrenia. Knockdown mice have also been produced for the NR1 and NR2A subtype of NMDA glutamate receptors. These transgenic mice show behavioral abnormalities that are similar to those treated with NMDA receptor antagonists such as PCP, which are attenuated by antipsychotic drugs.

Spontaneous. Since schizophrenia may result in part from mutations present in nature, an animal with a spontaneous mutation that shares some resemblance to schizophrenia would be of interest. The reeler mouse is a spontaneous mutant that has been around for over 30 years and has been extensively studied to understand the role of reelin in development. The heterozygous reeler mouse, which like patients with schizophrenia only expresses half of the normal levels of reelin, has recently emerged as a possible model of schizophrenia vulnerability. These mice have many neuroanatomi-cal abnormalities that resemble those found in the brains of patients with schizophrenia, including decreased neuropil volume, increased cell packing density, decreased dendritic spine density, mis-migration of NADPH-diaphorase cells, and decreased GAD67 mRNA and protein expression. These mice also show similar behavioral abnormalities including gating deficits (PPI), cognitive deficits (slow acquisition rate in radial maze task), increased anxiety in the elevated plus-maze test, and olfactory discrimination deficits (Costa et al., 2002). Further study of these mice may identify them as a good model to develop new therapeutic agents for the treatment of this disease.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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