Disturbances in the FGFR1-5-HT1A heteroreceptor complexes in the raphe-hippocampal 5-HT system develop in a genetic rat model of depression

Dasiel O. Borroto-Escuela, Caitlin M. Dupont, Xiang Li, David Savelli, Davide Lattanzi, Ipsit Srivastava, Manuel Narváez, Michael Di Palma, Elisa Barbieri, Yuniesky Andrade-Talavera, Riccardo Cuppini, Yuji Odagaki, M. Palkóvits, Patrizia Ambrogini, Maria Lindskog, Kjell Fuxe

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Abstract

The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.

Original languageEnglish
Article number309
JournalFrontiers in Cellular Neuroscience
Volume11
DOIs
Publication statusPublished - Oct 10 2017

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8-Hydroxy-2-(di-n-propylamino)tetralin
Genetic Models
Serotonin
Sprague Dawley Rats
Fibroblast Growth Factor 2
Serotonin 5-HT1 Receptor Agonists
Ligation
Antidepressive Agents
Hippocampus
Protein Subunits
Inwardly Rectifying Potassium Channel
Autoreceptors
Neuronal Plasticity
hydroxide ion
GTP-Binding Proteins
Neurons

Keywords

  • 5-HT1A receptor
  • Depression
  • Dimerization
  • Fibroblast growth factor receptor 1
  • Heteroreceptor complexes
  • Hippocampus
  • Raphe
  • Receptor-receptor interaction

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Disturbances in the FGFR1-5-HT1A heteroreceptor complexes in the raphe-hippocampal 5-HT system develop in a genetic rat model of depression. / Borroto-Escuela, Dasiel O.; Dupont, Caitlin M.; Li, Xiang; Savelli, David; Lattanzi, Davide; Srivastava, Ipsit; Narváez, Manuel; Di Palma, Michael; Barbieri, Elisa; Andrade-Talavera, Yuniesky; Cuppini, Riccardo; Odagaki, Yuji; Palkóvits, M.; Ambrogini, Patrizia; Lindskog, Maria; Fuxe, Kjell.

In: Frontiers in Cellular Neuroscience, Vol. 11, 309, 10.10.2017.

Research output: Contribution to journalArticle

Borroto-Escuela, DO, Dupont, CM, Li, X, Savelli, D, Lattanzi, D, Srivastava, I, Narváez, M, Di Palma, M, Barbieri, E, Andrade-Talavera, Y, Cuppini, R, Odagaki, Y, Palkóvits, M, Ambrogini, P, Lindskog, M & Fuxe, K 2017, 'Disturbances in the FGFR1-5-HT1A heteroreceptor complexes in the raphe-hippocampal 5-HT system develop in a genetic rat model of depression', Frontiers in Cellular Neuroscience, vol. 11, 309. https://doi.org/10.3389/fncel.2017.00309
Borroto-Escuela, Dasiel O. ; Dupont, Caitlin M. ; Li, Xiang ; Savelli, David ; Lattanzi, Davide ; Srivastava, Ipsit ; Narváez, Manuel ; Di Palma, Michael ; Barbieri, Elisa ; Andrade-Talavera, Yuniesky ; Cuppini, Riccardo ; Odagaki, Yuji ; Palkóvits, M. ; Ambrogini, Patrizia ; Lindskog, Maria ; Fuxe, Kjell. / Disturbances in the FGFR1-5-HT1A heteroreceptor complexes in the raphe-hippocampal 5-HT system develop in a genetic rat model of depression. In: Frontiers in Cellular Neuroscience. 2017 ; Vol. 11.
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AU - Borroto-Escuela, Dasiel O.

AU - Dupont, Caitlin M.

AU - Li, Xiang

AU - Savelli, David

AU - Lattanzi, Davide

AU - Srivastava, Ipsit

AU - Narváez, Manuel

AU - Di Palma, Michael

AU - Barbieri, Elisa

AU - Andrade-Talavera, Yuniesky

AU - Cuppini, Riccardo

AU - Odagaki, Yuji

AU - Palkóvits, M.

AU - Ambrogini, Patrizia

AU - Lindskog, Maria

AU - Fuxe, Kjell

PY - 2017/10/10

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N2 - The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.

AB - The FGFR1-5-HT1A heteroreceptor complexes are involved in neuroplasticity in the rat hippocampus and in the mesencephalic raphe 5-HT nerve cells. There exists a 5-HT1A protomer enhancement of FGFR1 protomer signaling. Acute and 10 day treatment with intracerebroventricular (i.c.v.) FGF-2 and the 5-HT1A agonist 8-OH-DPAT produced enhanced antidepressant effects in the forced swim test (FST). We studied in the current work the disturbances in the FGFR1-5-HT1A heterocomplexes in a genetic rat model of depression, the Flinders sensitive line (FSL) rats of Sprague-Dawley (SD) origin, by means of neurochemical, neurophysiological and behavioral techniques. In control SD rats, the FGFR1 agonist SUN11602 and FGF2 produced a significant reduction of G protein-coupled inwardly rectifying K+ channel (GIRK) currents induced by 8-OH-DPAT in the CA1 area of the hippocampus. In FSL rats, only i.c.v. 8-OH-DPAT alone treatment produced a significant reduction in the immobility time. The combined i.c.v. treatment (FGF2 + 8-OH-DPAT) in FSL rats did not cause a significant decrease in immobility time in the FST. However, in the SD rats this combined treatment produced a significant reduction. Furthermore, in the FSL rat a significant increase in the density of FGFR1-5-HT1A proximity ligation assay (PLA) positive clusters was only found after i.c.v. 8-OH-DPAT treatment alone in the CA2 and CA3 areas. In the SD rat a significant increase in the density of specific PLA clusters was only observed in the CA2 area of the i.c.v. combined treatment (FGF2 + 8-OH-DPAT) group. No treatment led to significant changes in the PLA clusters of the dorsal raphe in the FSL rat. However, significant changes in the density of specific PLA clusters were only found in the dorsal raphe of SD rats after combined treatment and treatment with 8-OH-DPAT alone. The results indicate that in FSL rats compared with SD rats alterations may develop in the ability of 8-OH-DPAT and combined FGFR1 and 5-HT1A agonist treatment to increase the density of FGFR1-5-HT1A heteroreceptor complexes of the dorsal raphe. It is proposed that such deficits in FSL rats may possibly reflect a failure of the combined agonist treatment to uncouple the 5-HT1A autoreceptors from the GIRK channels. This may contribute to the failure of producing antidepressant-like effects in the FSL rat by combined agonist treatment as seen in the SD rat. The antidepressant-like effects seen with the 5-HT1A agonist alone treatment in FSL but not in SD rats may instead involve significant increases in the FGFR1-5-HT1A complexes of the CA2 and CA3 areas of the hippocampus.

KW - 5-HT1A receptor

KW - Depression

KW - Dimerization

KW - Fibroblast growth factor receptor 1

KW - Heteroreceptor complexes

KW - Hippocampus

KW - Raphe

KW - Receptor-receptor interaction

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