Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity


  • J. Waider
  • S. Popp
  • B. Mlinar
  • A. Montalbano
  • F. Bonfiglio
  • B. Aboagye
  • E. Thuy
  • R. Kern
  • C. Thiel
  • N. Araragi
  • E. Svirin
  • A.G. Schmitt-Böhrer
  • R. Corradetti
  • C.A. Lowry
  • K.P. Lesch


  • Frontiers in Neuroscience


  • Front Neurosci 13: 245


  • Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.