From "bedside" to "bench" and back: A translational approach to studying dopamine dysfunction in schizophrenia

Abstract

Despite multiple lines of research, a mechanistic understanding of schizophrenia remains elusive. Neuroimaging studies have yielded observations that can be used in translational studies in animals to attempt to uncover their cellular and circuit basis and their significance for the diseased human brain. Enhanced D2 stimulation in the striatum is a well replicated and established observation in patients with schizophrenia. This "bedside" observation was reproduced "at the bench" level by creating a transgenic mouse overexpressing D2 receptors in dorsal striatum (D2R-OE mouse). The D2R-OE mouse showed multiple behavioral, molecular, electrophysiological and anatomical alterations. Some of these are consistent with findings in patients with schizophrenia, providing construct validity to the model and mechanistic insights for the observations made in humans. Other findings were novel, and provide an opportunity for a reverse translational effort back into the clinic. In this review we will summarize the process of translation and back translation from the D2R-OE mouse and describe the insights into the pathophysiology of the disease gained through this type of translational work.

Keywords: Cortex; D2; Dopamine; Mouse model; PET imaging; Schizophrenia; Striatum; Translation and back-translation.