Global analysis of gene and protein expression in rat models of depression with analysis of gene-environment interaction and antidepressant effects.

Background and aims: The simultaneous and wide-scale analysis of gene and protein expression provides a powerful strategy for the exploration at molecular level of complex pathophysiological mechanisms, such as the response to treatment with psychotropic agents. GENDEP is an Integrated Project that combines large-scale clinical pharmacogenomic studies on depressed patients with preclinical investigations on animal models, focusing on treatment with proserotonergic and pronoradrenergic antidepressants. Methods: Two different, complementary rat models of depression were used: the flinders sensitive line (FSL) and the learned helplessness. FSL rats were additionally subjected to a maternal separation protocol to investigate the impact of gene-environment interaction. Animals were chronically treated with escitalopram or nortriptyline, with behavioural studies and transcriptomic and proteomic profiling, in order to identify novel genes and gene products differentially expressed in the different paradigms. Transcriptome analyses were performed from prefrontal cortex and hippocampus using Affymetrix GeneChips, whilst for proteomics two-dimensional electrophoresis with mass spectrometry was used. Further proteomic studies, including functional investigations focusing on the detection of protein phosphorylation changes, were performed on both total extracts and purified synaptic terminals. Finally, modifications of synaptic plasticity (LTP) in hippocampus were investigated by electrophysiology with parallel measurements of molecular correlates. Results and conclusions: Preliminary results on proteome and transcriptome analysis of escitalopram treated rats allowed the identification of molecular and functional correlates of vulnerability to the disease, the effect of early-life stress and the response to pharmacological treatment