title: Impaired chemosensitivity of mouse dorsal raphe serotonergic neurons overexpressing serotonin 1A (Htr1a) receptors.
abstract: BACKGROUND
  Serotonergic system participates in a wide range of physiological processes and behaviors, but its role is generally considered as modulatory and noncrucial, especially concerning life-sustaining functions. We recently created a transgenic mouse line in which a functional deficit in serotonin homeostasis due to excessive serotonin autoinhibition was produced by inducing serotonin 1A receptor (Htr1a) overexpression selectively in serotonergic neurons (Htr1a raphe-overexpressing or Htr1a(RO) mice). Htr1a(RO) mice exhibit episodes of autonomic dysregulation, cardiovascular crises and death, resembling those of sudden infant death syndrome (SIDS) and revealing a life-supporting role of serotonergic system in autonomic control. Since midbrain serotonergic neurons are chemosensitive and are implicated in arousal we hypothesized that their chemosensitivity might be impaired in Htr1a(RO) mice.
  
  
  RESULTS
  Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1a(RO) mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO(2) produced an increase in firing rate of serotonergic neurons (0.260 ± 0.041 Hz, n=20, p=0.0001) and application of 3% CO(2) decreased their firing rate (-0.142 ± 0.025 Hz, n=17, p=0.0008). In contrast, in Htr1a(RO) mice, firing rate of serotonergic neurons was not significantly changed by 9% CO(2) (0.021 ± 0.034 Hz, n=16, p=0.49) and by 3% CO(2) (0.012 ± 0.046 Hz, n=12, p=0.97).
  
  
  CONCLUSIONS
  Our findings support the hypothesis that chemosensitivity of midbrain serotonergic neurons provides a physiological mechanism for arousal responses to life-threatening episodes of hypercapnia and that functional impairment, such as excessive autoinhibition, of midbrain serotonergic neuron responses to hypercapnia may contribute to sudden death.
authors.affiliation: Department of Preclinical and Clinical Pharmacology "Mario Aiazzi-Mancini" University of Florence, Florence, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Baccini
authors.forename: Boris
authors.initials: B
authors.lastname: Mlinar
authors.forename: Enrica
authors.initials: E
authors.lastname: Audero
authors.forename: Cornelius Thilo
authors.initials: CT
authors.lastname: Gross
authors.forename: Renato
authors.initials: R
authors.lastname: Corradetti
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006935:Hypercapnia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D044282:Receptor, Serotonin, 5-HT1A; D002245:Carbon Dioxide; D009638:Norepinephrine