Antidepressant-like effects of ketamine in a mouse model of serotonergic dysfunction

Traditional monoaminergic treatments of depression frequently exhibit suboptimal tolerability and effectiveness. The 'short' (s) allele variant of 5-HTTLPR is known to compromise transcriptional efficacy of the serotonin transporter (5-HTT) and can reduce treatment response to traditional antidepressants (e.g. selective serotonin reuptake inhibitors or SSRIs). This study sought to establish the 5-HTT knock-out (KO) line as a mouse model of SSRI-resistant depression and assess its response to a novel glutamatergic antidepressant, ketamine, a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist. Following acute antidepressant treatment, 5-HTT KO mice and wild-type (WT) controls were subjected to the forced-swim test (FST), one of the most widely used techniques to detect acute antidepressant response. As hypothesised, when assessed 30 min after administration in the FST, the SSRI sertraline (20 mg/kg, i.p.) produced antidepressant-like effects in WT control but not in 5-HTT KO mice. In contrast, ketamine (20 mg/kg, i.p.) induced antidepressant-like effects in both genotypes. 5-HTT KO mice also exhibited a reduced locomotor response to both MK-801 (another NMDAR antagonist) and ketamine, and reduced GluN2A protein levels in the hippocampus, suggesting glutamatergic dysfunction in this model. These results highlight the utility of 5-HTT KO mice as a relevant model of SSRI-resistant depression and demonstrate that ketamine can produce acute antidepressant-like effects in conditions of 5-HTT deficiency. These findings extend existing literature that indicates ketamine is effective in ameliorating symptoms of treatment-resistant depression and may have implications for understanding the cellular and molecular mechanisms underlying the antidepressant effects of ketamine. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.