FGFR1-5HT1AR heteroreceptor complexes differently modulate GIRK currents in the hippocampus and the raphe nucleus of control rats and of a genetic rat model of depression

The midbrain raphe serotonin neurons provide the main ascending serotonergic projection to the forebrain, including the hippocampus, which has a recognized role in the pathophysiology of depressive disorder. The activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels by serotonin 5HT1A receptors at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons reduces neuronal activity. The presence of FGFR1-5HT1A heteroreceptor complexes in this raphe-hippocampal serotonin neuron system has been demonstrated, but functional receptor-receptor interactions in the heterocomplexes have only been studied in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the present research, the short-term effects of FGFR1-5HT1A complex activation were studied in hippocampal pyramidal neurons, both in CA1 and CA2 areas, and midbrain dorsal raphe serotonergic neurons of SD rats and a genetic rat model of depression, the Flinders sensitive line (FSL) rats selected from SD strain, using an electrophysiological technique. The results obtained demonstrate that FGFR1-5HT1A heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels via the allosteric inhibitory interplay produced by agonist activation of the FGFR1 protomer, resulting in increased neuronal firing in the raphe-hippocampal 5HT system of SD rats. In contrast, apart from CA2 neurons, the inhibitory allosteric effects of FGFR1 agonist on the 5HT1AR protomer were unable to have this influence on GIRK channels in FSL rats. According to these data, 5HT1AR activation impaired hippocampal plasticity in both SD and FSL rats, as determined by long-term potentiation induction capability in the CA1 field, but not in SD rats following simultaneous FGFR1-5HT1A heterocomplex activation. While, due to the impairment in heterocomplex activation, long-term potentiation was precluded in FSL rats. It is thus hypothesized that in the genetic FSL model of depression, there is a considerable decrease of the allosteric inhibition mediated by the FGFR1 protomer on the 5HT1AR protomer, resulting in a reduced opening of the GIRK channels in the raphe-hippocampal serotonin pathway. The consequent increase in inhibition in dorsal raphe 5HT nerve cells and glutamatergic hippocampal CA1 pyramidal nerve cell firing may contribute to the onset of major depression.