New insights into the treatment of depression: role of girk channels and the glutamatergic antagonist ketamine in the neurophysiology of the dorsal raphe nucleus

Abstract

The thesis work is focused on the characterization of the neurophysiology of dorsal raphe neurons and the behavioral response in depression-related tests in mice lacking GIRK2 subunits and study of the effect of ketamine in the glutamatergic transmission of the dorsal raphe. The findings show the specific role of GIRK2 subunit- containing GIRK channels in the promotion of a depression-resistant phenotype, as well as their control of the tonic neuronal activity and mediation of the 5-HT1A receptor inhibitory responses. Moreover, the results show the involvement of GIRK2 subunit-containing GIRK channels in the behavioral response to the selective serotonin reuptake inhibitor citalopram. This could lead to development of new strategies targeting the 5- HT1A-GIRK2 pathway with great therapeutic interest for the study of pathologies related to an altered 5-HT transmission as in major depression. In addition, it is also investigated the possible role for glutamatergic transmission to alter electrophysiological properties of dorsal raphe neurons. Previous evidence indicates that glutamatergic antagonists as ketamine are emerging as new therapies for treatment of depressive symptoms. In conclusion this thesis shows that the pharmacological blockade or deletion of the GIRK2 subunit could limit the occurrence of depression-related behaviors, and specifically addressing GIRK2 subunits in the DR could give rise to new antidepressant therapies. Additionally, the dorsal raphe composes a target for new therapeutic strategies aimed at the interactions of the serotonin-glutamate transmission.