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The Journal of Neuroscience, November 11, 2009, 29(45):14271-14286; doi:10.1523/JNEUROSCI.3930-09.2009

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Neurobiology of Disease
A Selective Allosteric Potentiator of the M₁ Muscarinic Acetylcholine Receptor Increases Activity of Medial Prefrontal Cortical Neurons and Restores Impairments in Reversal Learning

Jana K. Shirey,^1 * Ashley E. Brady,^1 * Paulianda J. Jones,¹ Albert A. Davis,⁴ Thomas M. Bridges,¹ J. Phillip Kennedy,² Satyawan B. Jadhav,¹ Usha N. Menon,¹ Zixiu Xiang,¹ Mona L. Watson,^6,7 Edward P. Christian,⁵ James J. Doherty,⁵ Michael C. Quirk,⁵ Dean H. Snyder,⁵ James J. Lah,⁴ Allan I. Levey,⁴ Michelle M. Nicolle,^6,7 Craig W. Lindsley,^1,2,3 and P. Jeffrey Conn^1,3

¹Departments of Pharmacology and ²Chemistry, ³Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, ⁴Center for Neurodegenerative Disease and Department of Neurology, Emory University, Atlanta, Georgia 30322, ⁵Department of Neuroscience, AstraZeneca Pharmaceuticals, Wilmington, Delaware, 19850-5437, and ⁶Departments of Internal Medicine/Gerontology and ⁷Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157

Correspondence should be addressed to P. Jeffrey Conn, Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, 2215B Garland Avenue, 1215D Light Hall, Nashville, TN 37232-0697. Email: jeff.conn{at}vanderbilt.edu

M₁ muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M₁ receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M₁ receptor affinity for acetylcholine. We found that activation of the M₁ receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M₁ receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M₁ receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M₁ receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M₁ mAChR subtype may ameliorate impairments in cognitive function.

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Received Aug. 11, 2009; accepted Sept. 8, 2009.

Correspondence should be addressed to P. Jeffrey Conn, Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, 2215B Garland Avenue, 1215D Light Hall, Nashville, TN 37232-0697. Email: jeff.conn{at}vanderbilt.edu

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