Regulations of neuronal plasticity by the Nogo system

Abstract: Our brain has a lifelong capacity to create new memories, to learn and to adapt. This is due to the ability of neurons to modify their signaling depending on the situation to which the nervous system is exposed. The neurons of the CNS have despite this plasticity, a very limited ability to grow and recover if damaged. The lack of recovery is partly due to the presence of growth inhibitory molecules. This thesis approaches the control of nerve growth plasticity provided by Nogo-type signaling. Nogo receptor 1 (NgR1) is a key receptor for Nogo, MAG and OMgp. In Paper I, transgenic mice with forebrain overexpression of NgR1 were used. These mice did not differ from controls at baseline when investigating behavior and gross anatomy. However, a series of testing showed that NgR1 overexpression impairs memory consolidation and affects underlying neuronal microanatomy affecting both shape and number of synapses, as well as size of individual neurons. Paper II reveals that genes involved in Nogo-type signaling have individual and region dependent expression patterns in the brain. The expression of mRNA species differs depending on age, from a plastic youth to a rigid adulthood. The results could reflect how our ability to learn and heal changes over the course of life. Since Nogo-type signaling is important for a healthy brain, Paper III investigated whether a differently expressed Nogo system might contribute to disease. Strong repeated neuronal activity has been shown to cause lasting changes and this is the hallmark of migraine. While structural changes have indeed been found in migraine patients its pathophysiology remains elusive. Although, when a possible link was investigated between 749 migraine patients and SNPs in key genes contributing to Nogo-type signaling, no correlation between migraine and these genes was found. Paper IV investigates the psychedelic substance psilocybin, and its ability to affect plasticity. Psilocybin is a serotonin receptor agonist, currently increasingly investigated worldwide. The interest concerns whether psilocybin should have a role in the treatment of illnesses hitherto lacking accurate therapy, e.g. addiction and depression. However, few studies are available or being conducted regarding the effects of psilocybin on neurons and their function. In paper IV, a rapid and robust effect of psilocybin on pre- and postsynaptic markers is demonstrated. This suggests a similar effect on synaptic activity. In conclusion, this thesis addresses structural synaptic plasticity of the brain from different perspectives, and from preclinical to clinical. It emphasizes the relevance of Nogo-type signaling in terms of both behavior and microstructure of the brain. It also highlights psilocybin as an interesting serotonin receptor agonist to study further, in the quest to unravel what controls and affects our indispensable structural synaptic plasticity. To understand what regulates plasticity would unlock possibilities to treat neurological conditions such as stroke and traumatic brain injuries.