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 Htr1aRO mice). Htr1aRO 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 Htr1aRO mice. Principal findings Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1aRO mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO2 produced an increase in firing rate of serotonergic neurons (0.260±0.041 Hz, n = 20, p = 0.0001) and application of 3% CO2 decreased their firing rate (−0.142±0.025 Hz, n = 17, p = 0.0008). In contrast, in Htr1aRO mice, firing rate of serotonergic neurons was not significantly changed by 9% CO2 (0.021±0.034 Hz, n = 16, p = 0.49) and by 3% CO2 (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.

Impaired Chemosensitivity of Mouse Dorsal Raphe Serotonergic Neurons Overexpressing Serotonin 1A (Htr1a) Receptors / Gilda Baccini;Boris Mlinar;Enrica Audero;Cornelius Thilo Gross;Renato Corradetti. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 7:(2012), pp. e45072-0. [10.1371/journal.pone.0045072]

Impaired Chemosensitivity of Mouse Dorsal Raphe Serotonergic Neurons Overexpressing Serotonin 1A (Htr1a) Receptors

BACCINI, GILDA;MLINAR, BORIS;CORRADETTI, RENATO
2012

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 Htr1aRO mice). Htr1aRO 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 Htr1aRO mice. Principal findings Loose-seal cell-attached recordings in brainstem slices revealed that serotonergic neurons in dorsal raphe nucleus of Htr1aRO mice have dramatically reduced responses to hypercapnic challenge as compared with control littermates. In control mice, application of 9% CO2 produced an increase in firing rate of serotonergic neurons (0.260±0.041 Hz, n = 20, p = 0.0001) and application of 3% CO2 decreased their firing rate (−0.142±0.025 Hz, n = 17, p = 0.0008). In contrast, in Htr1aRO mice, firing rate of serotonergic neurons was not significantly changed by 9% CO2 (0.021±0.034 Hz, n = 16, p = 0.49) and by 3% CO2 (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.
2012
7
e45072
0
Gilda Baccini;Boris Mlinar;Enrica Audero;Cornelius Thilo Gross;Renato Corradetti
File in questo prodotto:
File Dimensione Formato  
Baccini 2012 journal.pone.0045072.pdf

accesso aperto

Tipologia: Versione finale referata (Postprint, Accepted manuscript)
Licenza: Open Access
Dimensione 387.25 kB
Formato Adobe PDF
387.25 kB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/772713
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 8
social impact