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Cerebral Cortex Advance Access published online on August 7, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp161
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Activation of Muscarinic Acetylcholine Receptors Induces a Nitric Oxide–Dependent Long-Term Depression in Rat Medial Prefrontal Cortex

Chiung-Chun Huang1 and Kuei-Sen Hsu1,2

1 Department of Pharmacology, College of Medicine, 2 Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan

Address correspondence to Dr Chiung-Chun Huang, Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan. Email: Chun2003{at}yahoo.com.tw.

Cholinergic neurotransmission in the medial prefrontal cortex (mPFC) is critical for normal processing of cue detection and cognitive performance. However, the mechanism by which cholinergic system modifies mPFC synaptic function remains unclear. Here we show that activation of muscarinic acetylcholine receptors (mAChRs) by carbamoylcholine (CCh) induces long-term depression (CCh-LTD) of excitatory synaptic transmission on mPFC layer V pyramidal neurons. The induction of CCh-LTD is dependent on M1 mAChR activation but does not require N-methyl-D-aspartate receptor activation or coincident synaptic stimulation. Activation of phospholipase C (PLC), protein kinase C (PKC), and postsynaptic Ca2+ release from inositol 1,4,5-triphosphate (IP3) receptor–sensitive internal stores are required for CCh-LTD induction. The expression of CCh-LTD is likely to be presynaptic because it is accompanied by a decrease in 1/(coefficient of variance)2 and an increase in synaptic failure and paired-pulse ratio of synaptic responses. CCh-LTD is blocked by nitric oxide (NO) synthase inhibitors, soluble guanylyl cyclase (sGC) inhibitor, and protein kinase G (PKG) inhibitor. Synaptic stimulation of M1 mAChRs with prolonged paired-pulse low-frequency stimulation also triggers LTD. These results suggest that activation of M1 mAChRs can induce LTD on mPFC layer V pyramidal neurons through the activation of postsynaptic PLC/PKC/IP3 receptor- and subsequently presynaptic NO/sGC/PKG-dependent signaling processes.

Key Words: glutamate • long-term depression • medial prefrontal cortex • muscarinic acetylcholine receptor • nitric oxide


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