Abstract
Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity.Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.
Highlights
While lasting memories are the result of a large number of interacting mechanisms, there is strong evidence that the final executive representation of a lasting memory is an altered structure of the neuronal network
Using different protocols targeting DA release and kinetics monitored by in vivo chronoamperometry, we find that potassium chloride (KCl)and amphetamine-induced increase of extracellular DA levels in the dorsal striatum is markedly less in Nogo receptor 1 (NgR1)-overexpressing mice and that KCl-induced release of DA is instead increased in mice lacking NgR1
When the system was naive, control mice released >5 times the amount of DA released by NgR1-overexpressing mice (p < 0.0001; Figures 2A,E,F)
Summary
While lasting memories are the result of a large number of interacting mechanisms, there is strong evidence that the final executive representation of a lasting memory is an altered structure of the neuronal network. In vivo imaging of postsynaptic sites in rodents suggests that individual newly formed synapses can exist for years, as required if the altered. Memory formation is a delicate process where spines are created or removed, strengthened or weakened depending on need. The structural changes needed to form a specific memory occur across large parts of the cortex. These can all be reached at the same time by the ascending modulatory systems from the brain stem. A complex and precisely organized molecular machinery consisting of plasticity-enhancing and plasticity-inhibiting systems is necessary to implement the required structural reorganizations that permanently embed novel memories in the brain. Neuronal activity downregulates neuronal NgR1 (Josephson et al, 2003; Nordgren et al, 2013; Karlsson et al, 2017) and increases local plasticity, including dendritic complexity (Karlsson et al, 2016), while the inability to downregulate NgR1 impairs long-term memory (Karlén et al, 2009)
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