The Dopamine D5 Receptor Is Involved in Working Memory.

Gregory V Carr,David R Sibley,Francesco Papaleo,Federica Maltese,Daniel R Weinberger

doi:10.3389/fphar.2017.00666

Abstract

Pharmacological studies indicate that dopamine D1-like receptors (D1 and D5) are critically involved in cognitive function. However, the lack of pharmacological ligands selective for either the D1 or D5 receptors has made it difficult to determine the unique contributions of the D1-like family members. To circumvent these pharmacological limitations, we used D5 receptor homozygous (-/-) and heterozygous (+/-) knockout mice, to identify the specific role of this receptor in higher order cognitive functions. We identified a novel role for D5 receptors in the regulation of spatial working memory and temporal order memory function. The D5 mutant mice acquired a discrete paired-trial variable-delay T-maze task at normal rates. However, both and mice exhibited impaired performance compared to littermates when a higher burden on working memory faculties was imposed. In a temporal order object recognition task, exhibited significant memory deficits. No D5-dependent differences in locomotor functions and interest in exploring objects were evident. Molecular biomarkers of dopaminergic functions within the prefrontal cortex (PFC) revealed a selective gene-dose effect on Akt phosphorylation at Ser473 with increased levels in knockout mice. A trend toward reduced levels in CaMKKbeta brain-specific band (64 kDa) in compared to was also evident. These findings highlight a previously unidentified role for D5 receptors in working memory function and associated molecular signatures within the PFC.

Highlights

Dopaminergic signaling in the brain serves a critical role in cognitive functions (Nieoullon, 2002; Papaleo et al, 2008, 2012; Detrait et al, 2016)
We show that partial reduction (D+5 /−) as well as the complete absence (D−5 /−) of D5 receptors produces working memory and recency memory deficits suggesting a previously undetected direct role for D5 receptors in prefrontal cortex (PFC)-dependent higher order cognitive functions
We investigated whether D5 knockout mice might have working memory- and dopaminerelated molecular alterations within the mPFC (Papaleo et al, FIGURE 3 | D+5 /− mice have impaired temporal order memory. (A) The differences in the recognition index were not confounded by any differences in total exploration time during the test phase. (B) Unlike D+5 /+ and D−5 /−, D+5 /− mice have no preference for the object presented during sample phase 1, indicating deficits in temporal order memory. n = 8 in the D+5 /+ group, 15 in the D+5 /− group, and 11 in the D−5 /− group. ∗p < 0.05 compared to D+5 /+ and #p < 0.05 compared to hypothetical zero

Summary

Introduction

Dopaminergic signaling in the brain serves a critical role in cognitive functions (Nieoullon, 2002; Papaleo et al, 2008, 2012; Detrait et al, 2016) This is especially evident in higher order executive functions modulated by the prefrontal cortex (PFC) such as attentional control, working memory, cognitive flexibility, and decision-making (Robbins and Arnsten, 2009; Floresco, 2013; Papaleo et al, 2014). D5 Receptor in Working Memory memory, attention, and recency memory across multiple species (Sawaguchi and Goldman-Rakic, 1994; Müller et al, 1998; Aultman and Moghaddam, 2001; Lidow et al, 2003; Managò et al, 2016) Both D1-like and D2-like (D2, D3, D4) receptor families seem to be implicated in mediating the ability to shift between attentional sets (i.e., cognitive flexibility) (Floresco et al, 2006). In the cortex there is significant overlap between D1 and D5 receptor localization, and the D1 receptor is much more prevalent compared to the D5 receptor (Smiley et al, 1994; Khan et al, 2000), further impeding the investigation of the selective role of D5 receptors in cortex-dependent cognitive functions

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