Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice.

Background: The effects of chronic treatment with tricyclic antidepressant (desipramine, DMI) on the hippocampal transcriptome in mice displaying high and low swim stress-induced analgesia (HA and LA lines) were studied. These mice displayed different depression-like behavioral responses to DMI: stress-sensitive HA animals responded to DMI, while LA animals did not.

Results: To investigate the effects of DMI treatment on gene expression profiling, whole-genome Illumina Expression BeadChip arrays and qPCR were used. Total RNA isolated from hippocampi was used. Expression profiling was then performed and data were analyzed bioinformatically to assess the influence of stress susceptibility-specific phenotypes on hippocampal transcriptomic responses to chronic DMI. DMI treatment affected the expression of 71 genes in HA mice and 41 genes in LA mice. We observed the upregulation of Igf2 and the genes involved in neurogenesis (HA: Sema3f, Ntng1, Gbx2, Efna5, and Rora; LA: Otx2, Rarb, and Drd1a) in both mouse lines. In HA mice, we observed the upregulation of genes involved in neurotransmitter transport, the termination of GABA and glycine activity (Slc6a11, Slc6a9), glutamate uptake (Slc17a6), and the downregulation of neuropeptide Y (Npy) and corticotropin releasing hormone-binding protein (Crhbp). In LA mice, we also observed the upregulation of other genes involved in neuroprotection (Ttr, Igfbp2, Prlr) and the downregulation of genes involved in calcium signaling and ion binding (Adcy1, Cckbr, Myl4, Slu7, Scrp1, Zfp330).

Conclusions: Several antidepressant treatment responses are similar in individuals with different sensitivities to stress, including the upregulation of Igf2 and the genes involved in neurogenesis. However, the findings also reveal that many responses to antidepressant treatments, involving the action of individual genes engaged in neurogenesis, neurotransmitter transport and neuroprotection, depend on constitutive hippocampal transcriptomic profiles and might be genotype dependent. The results suggest that, when and if this becomes feasible, antidepressant treatment should take into consideration individual sensitivity to stress.