Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia
Hai-Ying Shen, … , Benjamin K. Yee, Detlev Boison
Hai-Ying Shen, … , Benjamin K. Yee, Detlev Boison
Published June 18, 2012
Citation Information: J Clin Invest. 2012;122(7):2567-2577. https://doi.org/10.1172/JCI62378.
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Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Abstract

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the “adenosine hypothesis” of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Authors

Hai-Ying Shen, Philipp Singer, Nikki Lytle, Catherine J. Wei, Jing-Quan Lan, Rebecca L. Williams-Karnesky, Jiang-Fan Chen, Benjamin K. Yee, Detlev Boison

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Figure 4

BHK cell–based adenosine augmentation approach.

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BHK cell–based adenosine augmentation approach. (A) Representative Weste...
(A) Representative Western blot from cell extracts of BHK-AK2 (completely lacking ADK expression) and BHK-WT cells (with normal ADK expression, as control) that were used for cell transplantations. Anti-tubulin immunoreactivity was used to normalize for equal loading, and recombinant ADK (rADK) was loaded for comparison. (B) Demonstration of adenosine release from BHK-AK2 cells, which released about 20 ng adenosine per 105 cells during the first hour of incubation. (C and D) Nissl staining of coronal brain sections from graft recipients 3 weeks after grafting into Adk-tg recipients validated the location of the graft (red arrows) in either (C, left) the striatum or (D) above the CA1 pyramidal cell layer of the hippocampal formation. ADK immunohistochemistry (C, right) demonstrated ADK expression in BHK-WT grafts (C, top right) but lack of ADK immunohistochemistry in BHK-AK2 grafts (C, bottom right). The locations of BHK-WT and BHK-AK2 cell grafts of each animal tested are shown superimposed on a standard mouse brain atlas image of the (E) striatum (AP, 1.00 mm from bregma) and (F) hippocampus (AP, –2.10 mm). The graphs by the atlas images indicate the average area of the corresponding cell grafts. Data are mean ± SEM. *P < 0.01, versus BHK-WT. Scale bar: 300 μm.