Alternative splicing dysregulation in mental disorders

Abstract

The brain's ability to adapt ultimately depends on the efficiency with which neuronal connections are made, destroyed, or manipulated. This connectivity is largely controlled by synaptic plasticity, which creates, strengthens, or weakens signals that are necessary for appropriate functioning of the organism. This constant rewiring allows an organism to learn, mature, and cope with the ever-changing environment. However, this rewiring is dependent on the ability to make new proteins, which highlights the importance of transcription, translation, and post-translational modification in the process of synaptic plasticity. Among these cellular functions, transcription plays a key role in providing the necessary variability that is required to regulate neurodevelopment and cognitive behaviors. During transcription, alternative splicing regulates the contents of transcriptomic elements by cutting and stitching the transcribed pre-mRNA and adjusting the configuration of the mature mRNA(s) to meet the necessary cellular requirements. Therefore, it is conceivable that alternative splicing abnormalities can result in inappropriate adjustment of the transcriptome and result in pathological adaptation. In this dissertation, I review the evidence of dysfunctional gene splicing in neuropsychiatric disorders. Then I evaluate the extent of alternative splicing in an animal model for social interaction. This model utilizes valproic acid exposure at a critical developmental period to illicit significant and long-lasting changes in social interaction behavior. Next, I explore the abundance and types of alternative-splicing dysregulationin postmortembrain tissue samples from schizophrenia patients as compared to non-psychotic comparison subjects. Finally, I describe the mechanisms by which a schizophrenia-associated polymorphism in a strong candidate gene (DRD2, which encodes the D2 dopamine receptor) disrupts alternative splicing and leads to inappropriate transcription that is associated with cognitive dysfunction. Collectively, these results reinforce the notion that consideration of genetic variants that dysregulate particular mRNA isoforms and understanding the biological consequence of expressing such isoforms is a crucial step in our efforts to understand human behavior and to develop therapeutic interventions for mental disorders.