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Science 333 (6049): 1642-1646

Copyright © 2011 by the American Association for the Advancement of Science

Role for the Membrane Receptor Guanylyl Cyclase-C in Attention Deficiency and Hyperactive Behavior

Rong Gong,1,2,* Cheng Ding,2,3,* Ji Hu,2,* Yao Lu,2 Fei Liu,4 Elizabeth Mann,5 Fuqiang Xu,4 Mitchell B. Cohen,5 Minmin Luo2,6,{dagger}

Abstract: Midbrain dopamine neurons regulate many important behavioral processes, and their dysfunctions are associated with several human neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3',5'-monophosphate–dependent protein kinase (PKG). Mice in which GC-C has been knocked out exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons.

1 Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
2 National Institute of Biological Sciences (NIBS), Beijing 102206, China.
3 College of Life Sciences, Beijing Normal University, Beijing 100875, China.
4 Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
5 Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
6 School of Life Sciences, Tsinghua University, Beijing 100084, China.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: luominmin{at}nibs.ac.cn

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