Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity

Neuropsychopharmacology. 2015 May;40(6):1471-84. doi: 10.1038/npp.2014.332. Epub 2014 Dec 30.


Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / physiopathology*
  • Brain / physiopathology*
  • Depression / physiopathology
  • Hydroxyindoleacetic Acid / metabolism
  • Learning / physiology
  • Male
  • Memory / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Norepinephrine / metabolism
  • Phenotype
  • Receptors, AMPA / deficiency*
  • Receptors, AMPA / genetics
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Serotonergic Neurons / physiology*
  • Serotonin / metabolism
  • Tryptophan Hydroxylase / metabolism


  • Receptors, AMPA
  • Receptors, Adrenergic, alpha-1
  • Serotonin
  • Hydroxyindoleacetic Acid
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase
  • glutamate receptor ionotropic, AMPA 1
  • Norepinephrine