Abstract: The adenosine system as a novel target substrate in suicide
Over 40,000 thousand people die by suicide each year in the US but few interventions consistently reduce suicidal thoughts and behaviors. Our limited understanding of the neurobiology of suicide hinders development of efficacious and safe interventions. Adenosine is a ubiquitously expressed neuromodulator that fine-tunes signaling in the brain. Perturbations in the expression and activity of the enzymes, transporters and receptors that make up the adenosine system are associated with many risk factors for suicide behavior. Dysregulation of the adenosine system is implicated in severe mental illnesses like major depression and schizophrenia, sleep disturbances, and increased impulsive behaviors which are associated with suicide. However, our limited understanding of the neurobiology of this complex, multi-functional modulatory system in suicide impedes the development of the adenosine system as a novel target for intervention in the treatment of suicide.
To date, the adenosine system has not been directly studied in subjects who died by suicide. This system offers an underdeveloped substrate for pharmacological targeting and its potential to modulate complex behaviors like suicide have yet to be exploited therapeutically. Studying the adenosine system will increase our understanding of the neurobiology of suicide and may lead to the development of novel interventions for suicide.
We propose to characterize the cell-subtype specific changes in the adenosine system in suicide. We will measure changes in the gene expression (quantitative polymerase chain reaction) and protein expression of the enzymes and transporters that are responsible for generating extracellular adenosine and the receptors that adenosine acts on. We will examine these targets in enriched populations of astrocytes, pyramidal neurons and inhibitory interneurons cut from the dorsolateral prefrontal cortex of subjects diagnosed with major depression who died by suicide and comparison groups (n=23 per group). The data generated from these experiments will then undergo bioinformatic analysis using the LINCS database. Connectivity mapping will link changes in patterns of gene expression that are induced by perturbations of the adenosine system found in suicide, with chemical perturbagens (drugs) that induce opposing patterns of change in gene expression. From this, we will infer drug treatments that will reverse the effect of alterations in the adenosine system in subjects who die by suicide. The results of examining the adenosine system in postmortem tissue will be highly translatable to patient populations.
Overall, our studies will advance our understanding of cell-subtype specific perturbations in the adenosine system in suicide, and of the underlying neurobiology of suicide in severe mental illness. This work will also generate novel substrates and potential pharmacological targets for intervention in suicide behavior.