Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation

Neuron. 2018 Jun 6;98(5):992-1004.e4. doi: 10.1016/j.neuron.2018.04.030. Epub 2018 May 10.


The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation.

Keywords: CA1; behavior; hippocampus; learning; memory; neuromodulation; optogenetics; plasticity; potentiation; serotonin.

Publication types

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

MeSH terms

  • Animals
  • Axons / metabolism
  • CA1 Region, Hippocampal / metabolism*
  • CA1 Region, Hippocampal / physiology
  • CA3 Region, Hippocampal / metabolism*
  • CA3 Region, Hippocampal / physiology
  • Hippocampus
  • Long-Term Potentiation
  • Memory
  • Mice
  • Neural Inhibition / physiology
  • Optogenetics
  • Receptors, Serotonin, 5-HT4 / metabolism*
  • Serotonergic Neurons / metabolism*
  • Serotonin / metabolism*
  • Serotonin / physiology
  • Spatial Memory / physiology*
  • Synaptic Transmission


  • Receptors, Serotonin, 5-HT4
  • Serotonin