Transient and Selective Overexpression of Dopamine D2 Receptors in the Striatum Causes Persistent Abnormalities in Prefrontal Cortex Functioning

Abstract

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…Studies have also suggested an increased affinity of D 2 receptors for DA in schizophrenia, which may produce D 2 receptor supersensitivity in the NAc, contributing to psychosis [79]. In an interesting animal model correlate to these studies, transient overexpression of D 2 receptors in the striatum of mice resulted in deficits in prefrontal working memory, resembling some of the features of human schizophrenia [80]. Studies such as these indicate that alterations in DA receptor expression (or function) can result in a dysfunctional reward system.…”

“…Kellendonk et al . [80] attempted to model this D 2 receptor elevation in genetically engineered mice, in which they transiently and selectively overexpressed D 2 receptors in the striatum including in the caudate putamen, the NAc, and olfactory tubercle. It was found that 30% of striatal MSNs overexpressed these engineered receptors, thereby elevating the D 2 receptor level to about 15% higher than that of normal mice.…”

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

“…The PFC receives key ascending dopaminergic inputs from the midbrain and other subcortical areas (Kellendonk et al., 2006; Tekin & Cummings, 2002), and emerging evidence suggests the existence of an optimal level of dopamine needed for efficient PFC functioning (Goldman‐Rakic, Muly, & Williams, 2000). Two genes that have been associated with various psychiatric and neurological disorders and which have attracted attention due to their role in cognitive and emotional processes are the genes encoding for the enzyme catechol‐O‐methyltransferase ( COMT ; Dickinson & Elvevåg, 2009; Scheggia, Sannino, Luisa Scattoni, & Papaleo, 2012; Tunbridge, Harrison, & Weinberger, 2006) and the dopamine receptor D2 ( DRD2 ; Frank & Fossella, 2011; Huertas, Bühler, Echeverry‐Alzate, Giménez, & López‐Moreno, 2012; Kellendonk et al., 2006).…”

“…Two genes that have been associated with various psychiatric and neurological disorders and which have attracted attention due to their role in cognitive and emotional processes are the genes encoding for the enzyme catechol‐O‐methyltransferase ( COMT ; Dickinson & Elvevåg, 2009; Scheggia, Sannino, Luisa Scattoni, & Papaleo, 2012; Tunbridge, Harrison, & Weinberger, 2006) and the dopamine receptor D2 ( DRD2 ; Frank & Fossella, 2011; Huertas, Bühler, Echeverry‐Alzate, Giménez, & López‐Moreno, 2012; Kellendonk et al., 2006). COMT is responsible for breaking down ~50–60% of dopamine produced in the frontal cortex (Yavich, Forsberg, Karayiorgou, Gogos, & Männistö, 2007).…”

“…D2 receptor availability in the caudate has been associated with performance on executive function tests requiring mental flexibility, abstraction, response inhibition and attention in healthy individuals (Volkow et al., 1998) and D2 receptor occupancy has been associated with vigilance and neurocognitive function in schizophrenia patients (Sakurai et al., 2012), whereas the blockade of D2 receptors by risperidone correlates with attentional deficits in schizophrenia (Uchida et al., 2009). Animal studies have shown that mutant mice lacking D2 receptors exhibit impaired spatial working memory and attentional abilities (Glickstein, DeSteno, Hof, & Schmauss, 2005; Glickstein, Hof, & Schmauss, 2002) and over‐expression of D2 receptors in striatum has similarly been associated with impaired working memory performance in mice (Kellendonk et al., 2006). The C957T (rs6277) polymorphism in the D2 receptor has recently gained interest due to its proposed role in the development of schizophrenia.…”