Insights About Striatal Circuit Function and Schizophrenia From a Mouse Model of Dopamine D2 Receptor Upregulation

Abstract

The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D₂ receptor selectively in the striatum. We review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D₂ receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients.

Keywords: D(2) receptor; Dopamine; Mouse model, Negative symptoms; Schizophrenia; Striatal circuit function.

Figure 1. Circuit abnormalities induced by striatal D2R upregulation

Left: Cortico-striatal circuitry in wild-type mice. The striatum is the input area of the basal ganglia receiving projections from cortex and thalamus. Via two functional opposing pathways, the direct (red) and indirect (blue) pathways it projects to the substantia nigra (SN) and ventral tegmental area (VTA) output nuclei of the basal ganglia. Dopaminergic neurons in the SN and VTA modulate activity in cortex, dorsal and ventral striatum. Right: Upregulation of D2Rs in the striatum led to several changes in this circuitry: 1) It enhanced the density of direct pathway collaterals in the GPe thereby affecting the functional balance between both pathways. 2) It decreases activity in dopaminergic neurons projecting to the cortex and ventral striatum but not to the dorsal striatum. 3) It decreases GABA transmission in the cortex.