Disturbances in the FGFR1-5-HT1A Heteroreceptor Complexes in the Raphe-Hippocampal 5-HT System Develop in a Genetic Rat Model of Depression

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.

Receptor–Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

“…The overall architecture of the global GPCR heterodimer network [ 10 ] shows a scale-free topology, because most protomers participate only in a couple of interactions. However, a few have more than ten connections (heterodimerization) to other GPCR protomers such as D2R and 5-HT1A receptors, in addition to direct interactions with receptor tyrosine kinase (RTK) [ 6 , 11 , 12 , 13 , 14 , 15 , 16 ] and ligand-gated ion channel receptors [ 17 , 18 , 19 ].…”

“…It is known from our work that 5-HT1AR forms heteromers with many other receptors in neuronal membranes of the brain linked to the ascending 5-HT neurons [ 6 , 11 , 13 , 34 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. They are of relevance for depression and its treatment.…”

“…They are of relevance for depression and its treatment. In this focused review, we will present an update of the work on the brain 5-HT1A–FGFR1 heteroreceptor complexes [ 6 , 11 , 13 , 14 , 39 , 40 ] and the demonstration of a novel 5-HT1A receptor complex: the brain 5-HT1A–5-HT2A isoreceptor complex [ 34 ]. The complex yet exciting world of brain GalR–5-HT1A heteroreceptor complexes will also be briefly discussed [ 37 , 42 , 43 , 45 ] ( Figure 1 ).…”

Brain Dopamine Transmission in Health and Parkinson's Disease: Modulation of Synaptic Transmission and Plasticity Through Volume Transmission and Dopamine Heteroreceptors

“…Activation of the GPCR protomer over time in such receptor complexes can also produce changes in synaptic plasticity by altering the balance of the different homo and heteroreceptor complexes in the postsynaptic membrane and/or changes in their allosteric receptor-receptor interactions (Borroto-Escuela et al, 2015b , 2016a , 2017a , b , c ; Feltmann et al, 2018 ). GPCR-RTK heteroreceptor complexes including their receptor-receptor interactions can also undergo dynamic changes in functional states and in diseases (Flajolet et al, 2008 ; Borroto-Escuela et al, 2013a , b , 2016c , 2017a ). Several molecular mechanisms can be in operation: changes in transcription e.g., of adaptor proteins, in internalization of receptor protomers, conformational changes in receptors reducing the affinity for each protomer with increased affinity for other receptors.…”

Receptor-Receptor Interactions in the Central Nervous System

“…These changes in the receptor protomers produce marked increases in diversity and bias of GPCR function. One emerging concept in neuropsychopharmacology is that a dysfunction of the allosteric receptor-receptor interactions contributes to disease progression in mental and neurological disorders [4][5][6][7][8][9][10]. So far their stoichiometry and topology are unknown within the heteromer formed as well as the number of adapter proteins participating, including their architecture.…”