When NO means no: translational genetics of the nitrinergic system

Munich Psychiatry Lecture Series | MPLS

  • Datum: 07.02.2017
  • Uhrzeit: 15:00 - 16:00
  • Vortragende(r): Andreas Reif
  • Goethe Universität, Frankfurt am Main
  • Ort: Max-Planck-Institut für Psychiatrie
  • Raum: Hörsaal
  • Gastgeber: Elisabeth Binder
  • Kontakt: binder@psych.mpg.de
When NO means no: translational genetics of the nitrinergic system

The NO system since long has been suggested to play a role in the pathogenesis of schizophrenia and impulsive behaviors. Evidence came from animal models as well as human postmortem studies; however, in recent years also human genetic data argued in favor of this hypothesis. From a pathophysiological point of view, NO generation by NOS-I at the glutamatergic post-synapse seems to be an important mechanism in schizophrenia. NOS-I coupling to the NMDA receptor is disrupted by the adapter protein NOS1AP (previously termed CAPON). Case-control association studies suggest that genetic risk variants in both genes interact to increase the risk towards schizophrenia, and also, cognitive functioning is associated with NOS1 polymorphisms. We thus asked about the functional consequences of changed expression of NOS1 and NOS1AP by using different recombinant adeno-associated virus (rAAV) vectors to interfere with NOS I <> PDZ-interaction. Indeed we could show that overexpression of NOS1AP leads to an absence of NOS-I at synaptic spines, acting synergistically with reduced NOS1 expression. Moreover, NOS1AP was shown to regulate dendritic spine development and dendrite patterning. Correspondingly, the resulting behavior mimicked schizophrenia-like symptoms. Taken together, these data suggest that blockade of NOS I <> PDZ-interaction at the glutamatergic post-synapse might have a role in the pathogenesis of schizophrenia.  On the other hand, genetic data and early animal studies argued that NOS1 also has a role in aggression and impulsivity. While genetic and imaging genetics studies are supporting an association of the gene with these phenotypes, the direction of effect (i.e., whether reduced or increased NO results in impulsivity is unclear). Initial mouse knockout studies suggested that lack of Nos1 goes along with increased aggression. However, when carefully replicating these experiments, we could no longer observe this behavior – n the contrary, Nos1 knockout mice were even less aggressive. In line with this, zebrafish in which nos1 was knocked down displayed by reduced aggression. Taken together our translational data suggest that NO signaling is compromised in impulsive-aggressive behavior, yet the precise mechanism is not known.

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