Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation

• Published in: European neuropsychopharmacology 2020-02, Vol.31, p.69-85
• Main Authors: Marchetti, Luca, Lauria, Mario, Caberlotto, Laura, Musazzi, Laura, Popoli, Maurizio, Mathé, Aleksander A., Domenici, Enrico, Carboni, Lucia
• Format: Article
• Language: English
• Subjects: Animals; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Bioinformatics; Citalopram - pharmacology; Citalopram - therapeutic use; Depressive Disorder, Treatment-Resistant - drug therapy; Depressive Disorder, Treatment-Resistant - genetics; Depressive Disorder, Treatment-Resistant - psychology; Disease Models, Animal; Escitalopram; Female; Forced swim test; Gene Expression; Hippocampus - drug effects; Major depressive disorder; Male; Maternal Deprivation; Medicin och hälsovetenskap; Nortriptyline; Protein Interaction Maps - drug effects; Protein Interaction Maps - genetics; Rats; Rats, Transgenic; Transcriptome - drug effects; Transcriptome - genetics; Treatment Outcome
• ISSN: 0924-977X; 1873-7862; 1873-7862
• DOI: 10.1016/j.euroneuro.2019.11.004

•Flinders sensitive rats received maternal separation and antidepressant treatment.•Maternal separation hampered response of reduced immobility after antidepressants.•Transcriptional signatures discriminated controls from antidepressant treated rats.•Distinct brain transcriptional signatures are associated with treatment response.•Antidepressant response genes contribute to elucidate treatment-resistant depression. Neurobiological underpinnings of treatment-resistant depression, a debilitating condition associated with significant functional impairment, have not been elucidated. Consequently, the aim of this study was to use animal models of response and resistance to antidepressant treatment, in an attempt to identify differences in associated transcriptional responses. Flinders Sensitive Line rats were subjected to maternal separation (MS) and chronically treated with Escitalopram or Nortriptyline. Antidepressants reduced immobility time in the forced swim test in non-MS rats, while lack of antidepressant behavioural response was observed in MS animals. We developed a novel bioinformatic algorithm that enabled identification of transcriptional signatures in hippocampus and pre-frontal cortex that discriminate vehicle- and antidepressant-treated subjects in both MS and non-MS rats. Functional annotation analysis showed that in antidepressant-responder rats the most enriched pathways included IQGAPs activation, toll-like receptor trafficking, energy metabolism, and regulation of endopeptidase activity. The analysis of interacting proteins implicated synaptic vesicles and neurotransmitter release, ubiquitin regulation, cytoskeleton organisation and carbohydrate metabolism. In contrast, in treatment-resistant MS rats, main expression changes were revealed in ribosomal proteins, inflammatory responses, transcriptional/epigenetic regulation, and small GTPases. Susceptibility signature shared Rtn1, Zdhhc5, Igsf6, and Sim1 genes with the latest depression GWAS meta-analysis, while antidepressant resistance signature shared Ctnnd1, Rbms3, Atp1a3, and Pla2r1 genes. In conclusion, this study demonstrated that distinct transcriptional signatures are associated with behavioural response or non-response to antidepressant treatment. The identification of genes involved in antidepressant response will increase the comprehension of the neurobiological underpinnings of treatment-resistant depression, thus contributing to identification of novel therapeutic targets.