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Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory

Abstract

Dopamine (DA) D1 receptor (D1R) stimulation in prefrontal cortex (PFC) produces an 'inverted-U' dose-response, whereby either too little or too much D1R stimulation impairs spatial working memory. This response has been observed across species, including genetic linkages with human cognitive abilities, PFC activation states and DA synthesis. The cellular basis for the inverted U has long been sought, with in vitro intracellular recordings supporting a variety of potential mechanisms. The current study demonstrates that the D1R agonist inverted-U response can be observed in PFC neurons of behaving monkeys: low levels of D1R stimulation enhance spatial tuning by suppressing responses to nonpreferred directions, whereas high levels reduce delay-related firing for all directions, eroding tuning. These sculpting actions of D1R stimulation are mediated in monkeys and rats by cyclic AMP intracellular signaling. The evidence for an inverted U at the cellular level in behaving animals promises to bridge in vitro molecular analyses with human cognitive experience.

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Figure 1: Inverted-U effects mediated by D1R agonists.
Figure 2: Effects of low doses of D1R agonists on the tuning profile of PFC neurons.
Figure 3: Suppressive effects of higher doses of D1R agonists.
Figure 4: Specificity of D1R agonist-mediated suppression and effects of antagonists on spatial tuning.
Figure 5: cAMP signaling in D1R agonist effects.
Figure 6: Effects of PKC inhibition on D1R agonist-mediated neuronal suppression.

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Acknowledgements

We would like to thank G. Leydon for help with Spike2 scripts and C.J. Bruce for assistance with surgical procedures and guidance with the research. We would like to thank S. Wilson, J. Carlson, M. Horn, L. Ciavarella, S. Johnson and T. Sadlon for veterinary assistance and help with surgeries. This research was supported by P50MH068789 to A.F.T.A.

Author information

Authors and Affiliations

Authors

Contributions

S.V. performed the D1R agonist dose-response experiments and second-messenger experiments. S.V. and M.W. performed the D1R high-dose experiments. S.G.B. provided the rat behavioral data. G.V.W. initiated the pilot experiments with D1R agonists. S.V. and A.F.T.A. wrote the manuscript. A.F.T.A. supervised the project.

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Competing interests

A.F.T.A. and Yale University have a patent application and license agreement with Marinus Pharmaceuticals for the use of chelerythrine for the treatment of bipolar disorder, schizophrenia and related disorders.

Supplementary information

Supplementary Fig. 1

Polar plot representation of the effects of D1 agonist SKF81297 (15nA) on the neuron in Fig 1B. (PDF 83 kb)

Supplementary Fig. 2

Statistical analysis of effects of low doses of D1R agonists on spatial spread of PFC neuronal memory activity. (PDF 109 kb)

Supplementary Fig. 3

Effects of the D1R antagonist SCH 23390 on delay activity of a PFC neuron. (PDF 97 kb)

Supplementary Fig. 4

Example of recovery after D1R agonist induced suppression of neuronal activity. (PDF 140 kb)

Supplementary Fig. 5

Population analysis of cAMP blockade preventing neuronal suppression by D1 agonist SKF38393. (PDF 134 kb)

Supplementary Fig. 6

Hypothesized model of the physiology of inverted U D1 receptor actions. (PDF 208 kb)

Supplementary Fig. 7

Recording area in PFC. (PDF 109 kb)

Supplementary Fig. 8

Effects of Na+ (saline) ejection on delay activity in PFC cells. (PDF 150 kb)

Supplementary Fig. 9

Comparison of the effects of Na+ ejection and D1 agonist ejection on PFC neuronal firing at various current strengths. (PDF 158 kb)

Supplementary Fig. 10

Effects of D1R stimulation on average delay activity adjusted for effects on baseline activity. (PDF 101 kb)

Supplementary Methods (PDF 69 kb)

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Vijayraghavan, S., Wang, M., Birnbaum, S. et al. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10, 376–384 (2007). https://doi.org/10.1038/nn1846

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