Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs

Abstract

BackgroundThe long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities.ResultsHere, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein.ConclusionsIn summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0458-4) contains supplementary material, which is available to authorized users.

Neuronal activity regulates alternative exon usage

“…This exon is used as an internal exon, but in the activity-regulated transcript as a terminal exon. A large number of Dclk1 splice variants regulated by alternative promotor usage have been described [38,46]. Only two transcripts comprise exon 9, and transcription of both is induced in the hippocampus by BDNF treatment [39] and by seizures [47,48] supporting the notion that different plasticity inducing stimuli trigger expression of the transcripts identified in this study.…”

Pharmaceutical Implications of Sex-Related RNA Divergence in Psychiatric Disorders

“…Notably, NEAT1 is regulated by the estrogen receptor [31], suggesting a potential sexual dimorphism for its function and/or its manipulation. In addition, NEAT1 levels are modified under treatment with a variety of drugs, including lipid-lowering agents [77] and psychotropic drugs [80]; such changes may affect the various functions of NEAT1, including those involving psychiatric disorders.…”

Aberrant alternative splicing of HTR2A exon II in peripheral blood lymphocytes of drug-naïve schizophrenic patients

“…Other researchers have shown the induction of the expression of certain isoforms of the Dclk1 kinase gene by means of antipsychotic drugs, which is involved in the synaptic plasticity and the neurogenesis processes, in the mouse's nucleus accumbens and the prefrontal cortex [ 12 ]. Drug-naïve first-episode schizophrenic patients were included in our study, which excludes the effect of antipsychotics on the expression of the gene isoforms, allowing the identified increased expression of the HTR2A transcript isoforms to be associated exclusively with mental illnesses.…”

“…Presently, the involvement of the alternative splice forms of the genes, which encode the neurotransmission proteins, in the pathogenesis of schizophrenia has been demonstrated [ 6 , 7 , 8 , 9 ]. Consequently, it has been shown that the administration of psychotropic drugs can affect the expression of the transcript isoforms [ 10 , 11 , 12 ].…”