Activation of muscarinic acetylcholine receptors induces a nitric oxide-dependent long-term depression in rat medial prefrontal cortex.
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 M(1) 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 Ca(2+) release from inositol 1,4,5-triphosphate (IP(3)) 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 M(1) mAChRs with prolonged paired-pulse low-frequency stimulation also triggers LTD. These results suggest that activation of M(1) mAChRs can induce LTD on mPFC layer V pyramidal neurons through the activation of postsynaptic PLC/PKC/IP(3) receptor- and subsequently presynaptic NO/sGC/PKG-dependent signaling processes.
Huang
Chiung-Chun
CC
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Chun2003@yahoo.com.tw
Hsu
Kuei-Sen
KS
D000818:Animals; D001703:Biophysics; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology / Q000502:physiology*; D011493:Protein Kinase C / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000494:pharmacology
D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D018377:Neurotransmitter Agents; D011976:Receptors, Muscarinic; D009569:Nitric Oxide; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D011493:Protein Kinase C; D010738:Type C Phospholipases