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The Journal of Neuroscience, July 2, 2003, 23(13):5762-5770

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Focal Deletion of the Adenosine A1 Receptor in Adult Mice Using an Adeno-Associated Viral Vector

Thomas E. Scammell,¹ Elda Arrigoni,¹ Margaret A. Thompson,² Patrick J. Ronan,³ Clifford B. Saper,^1,4 and Robert W. Greene³

¹Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, ²Division of Neuroscience, The Children's Hospital, Boston, Massachusetts 02115, ³Department of Psychiatry, University of Texas Southwestern Medical Center and Dallas Veterans Administration Medical Center, Dallas, Texas 75216, and ⁴Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

Adenosine is a ubiquitous neuromodulator that increases sleep, inhibits seizures, and promotes neuroprotection. Many of these effects are mediated by A1 receptors, but A1 receptors are expressed in most brain regions, and distinguishing the precise site of action of adenosine is challenging. To test the role of adenosine in different hippocampal regions, we have used the Cre-loxP system and an adeno-associated viral (AAV) vector to focally delete endogenous adenosine A1 receptors in the hippocampus. Microinjection of an AAV vector containing the gene for Cre recombinase induced intense, focal, neuron-specific recombination in reporter mice. In a separate line of mice with loxP sites flanking the major coding exon for the adenosine A1 receptor, this AAV-Cre markedly reduced A1 receptor mRNA and focally abolished the postsynaptic response to adenosine without any change in basic electrophysiologic properties. Adenosine inhibits signaling between CA3 and CA1 neurons, but it is unclear from pharmacologic studies whether this response is caused by presynaptic or postsynaptic effects. Deletion of A1 receptors from CA3 neurons abolished this response to adenosine, but deletion of A1 receptors from CA1 neurons had no effect, demonstrating a presynaptic site of action. This transduction knock-out technique holds enormous potential for dissecting the functions of different CNS pathways.

Key words: adenosine; A1 receptor; Cre recombinase; adeno-associated virus; AAV; electrophysiology; patch clamp

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Received Mar. 6, 2003; revised Mar. 6, 2003; accepted Apr. 14, 2003.

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