title: 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.
abstract: 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.
authors.affiliation: 1] Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany [2] Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Weber
authors.affiliation: Research Group Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Vogt
authors.affiliation: Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gartside
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Berger
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas (IDINE), Departamento de Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lujan
authors.affiliation: Biochemical Laboratory, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/HeidelbergUniversity, Mannheim, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lau
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.affiliation: Research Group Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D003863:Depression / Q000503:physiopathology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D018091:Receptors, AMPA / Q000172:deficiency* / Q000235:genetics; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D059326:Serotonergic Neurons / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D006897:Hydroxyindoleacetic Acid; D009638:Norepinephrine; D018091:Receptors, AMPA; D018340:Receptors, Adrenergic, alpha-1; D012701:Serotonin; D014365:Tryptophan Hydroxylase; C487802:Tph2 protein, mouse