Network analysis of gene expression in mice provides new evidence of involvement of the mTOR pathway in antipsychotic-induced extrapyramidal symptoms

Abstract

To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

“…However, basal differences, prior to treatment, between the two strains are independent of the drug and could explain the different susceptibility to EPS. This susceptibility could be common to different AP drugs, since the two strains have been phenotyped in response to haloperidol [24] and risperidone [9] As already mentioned, it is known that DRD2s are occupied by risperidone, blocking the indirect pathway. However, this antipsychotic drug is also characterized by a very high affinity for 5-HT2A receptors.…”

“…To address this issue, we analyzed the different populations of striatal Research Amalia Lafuente neurons and evaluated their mTOR-mediated response to risperidone in two mice strains with well-known different susceptibility to developing EPS [9,24].…”

“…These strains were selected from previous studies according to their EPS profile, one with susceptibility to developing EPS (A/J) and another with resistance (DBA/2J) [9,24]. To this end, we studied the phosphorylation pattern of ribosomal protein S6 (rpS6), which is phosphorylated at Ser235/236 and Ser244/247 residues by rps6 kinase, a major downstream effector of mTOR [25].…”

“…Previous work from our lab, using genome-wide gene expression analysis, revealed a connection between the development of EPS and the mTOR pathway in mice striatum and in peripheral blood of naïve patients suffering a first episode of psychosis [9][10][11]. Recently, various authors have implicated the mTOR signaling pathway in the modulation exerted by AP drugs such as thioridazine [12,13], olanzapine [14], haloperidol [15,16] and risperidone [17], among others.…”

“…A total of 24 male mice were used in the study (6 animals per group). The dose and time of administration are based on our previous work, where different doses of risperidone were tested using the same strains [9]. The dose selected for this study was the minimum dose used at which significant differences were observed in motor activity between the two strains [9].…”