Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11

Mol Psychiatry. 2013 Oct;18(10):1096-105. doi: 10.1038/mp.2012.130. Epub 2012 Oct 2.


Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / deficiency
  • Annexin A2 / genetics
  • Annexin A2 / physiology*
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology*
  • Depression / physiopathology
  • Disease Models, Animal
  • Emotions / physiology*
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Female
  • Genes, Reporter
  • Glutamic Acid / metabolism
  • Hippocampus / physiology*
  • Male
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Magnetic Resonance, Biomolecular
  • Phosphorylation / drug effects
  • Presynaptic Terminals / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Pyridines / pharmacology
  • Reaction Time
  • Receptor, Serotonin, 5-HT1B / physiology*
  • Receptors, AMPA / metabolism
  • Recombinant Fusion Proteins / metabolism
  • S100 Proteins / deficiency
  • S100 Proteins / genetics
  • S100 Proteins / physiology*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Transduction, Genetic


  • Annexin A2
  • CP 94253
  • Pyridines
  • Receptor, Serotonin, 5-HT1B
  • Receptors, AMPA
  • Recombinant Fusion Proteins
  • S100 Proteins
  • S100 calcium binding protein A10
  • Serotonin 5-HT1 Receptor Agonists
  • Glutamic Acid
  • glutamate receptor ionotropic, AMPA 1