BBB Seminar: Andreas Reif
Nitric oxide synthase-I (NOS-I) and brain function
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany
The gaseous messenger nitric oxide (NO) has been implicated in a wide range of behaviors. Behavioral phenotyping of mice lacking the neuronal isoform of nitric oxide synthase (NOS-I), the major source of NO in the CNS, revealed only little differences in activity-related parameters or depression-related tests, yet a subtle anxiolytic phenotype. The most prominent feature, however, is aggression and cognitive impairment. A set of >120 differentially expressed genes was identified; among the most significantly up-regulated genes were C/EBP - which binds to transcription factor binding sites in the promoter regions of human NOS1 exons 1c and 1f - and the glucocorticoid receptor. Adult neurogenesis was found to be altered in a specific manner: while the proliferation of neural stem cells was unchanged, the survival rates of newborn neurons were almost three times higher. This appears not to be mediated by brain-derived neurotrophic factor (BDNF), as BDNF mRNA and protein were unchanged in the hippocampus. However, there was a significant decrease of cortical BDNF protein.
Little is known about the function of NO in humans. We have identified a polymorphism in the transcriptional control region of NOS1 exon 1f and showed that this repeat alters gene expression; furthermore, it impacts on the transcriptome of brain tissue. Amongst the top dysregulated genes were alpha-synuclein and NMDA subunit 1. We aimed to investigate this polymorphism for an association with behavioral traits. Emphasis was placed on impulsive behaviors. Short NOS1 exon 1f alleles were significantly associated with Cluster B personality disorder, adult ADHD, violent crime, and suicide attempt and personality traits related to impulsivity. Notably, we observed a role for adverse environmental conditions in switching an initially positive effect of short NOS1 ex1f-alleles on impulsivity to maladaptive impulsivity. Finally, short promoter repeats appear to influence prefrontal brain functioning as tested by a CPT and ERPs. Collectively, these data argue for a role of NOS-I in human impulsive behavior and correlate to previous animal studies.
Host: Jan Haavik, Department of Biomedicine