Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice

PLoS One. 2010 Mar 4;5(3):e9529. doi: 10.1371/journal.pone.0009529.


Patients suffering from dementia of Alzheimer's type express less serotonin 4 receptors (5-HTR(4)), but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR(4) knock-out (KO) and wild-type (WT) mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR(4) control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR(4). Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg) to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR(4) KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT), the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR(4) KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR(4) KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR(4) to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR(4) aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR(4) mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety
  • Behavior, Animal
  • Locomotion
  • Male
  • Maze Learning
  • Memory
  • Memory, Long-Term
  • Memory, Short-Term
  • Mice
  • Mice, Knockout
  • Muscarinic Antagonists / pharmacology
  • Receptors, Muscarinic / metabolism*
  • Receptors, Serotonin, 5-HT4 / genetics*
  • Receptors, Serotonin, 5-HT4 / physiology*
  • Scopolamine / pharmacology


  • Muscarinic Antagonists
  • Receptors, Muscarinic
  • Receptors, Serotonin, 5-HT4
  • Scopolamine