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  • Final Report Summary - MEMORYSTICK (Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease)
ERC

MEMORYSTICK Report Summary

Project ID: 322744
Funded under: FP7-IDEAS-ERC
Country: Sweden

Final Report Summary - MEMORYSTICK (Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease)

Strong sensory inputs cause permanent alterations of the connections between nerve cells, the synaptic circuitry, and these alterations carry long term memories. Such structural synaptic plasticity is regulated by stimulating and inhibiting systems.
The nerve growth inhibitory Nogo signaling system consists of ligands, receptors, coreceptors and modulators. We showed that Nogo receptor 1 (NgR1) is down-regulated in activated nerve cells, and hypothesized that this renders neurons temporarily insensitive to the presence of inhibiting Nogo in their surroundings. This would unlock the gray matter memory bank, allowing novel synapses to form and new memories to be stored in the form of structural alterations of synaptic patterns.
The challenges that project MemoryStick intended to tackle were: "1. how neuronal activation is translated into lasting structural alterations" and "2. how plasticity and memory mechanisms become insufficient in aging, disease and injury". To accomplish this we studied wildtype mice, mice subjected to traumatic brain injury, mice with too much or no NgR1, mice with premature ageing, and mice with degeneration of dopamine (DA) nerve cells. We related behavior to genetic status and the structural appearance of brain nerve cells. To enable very detailed analysis of NgR1 location and regulation we also used long-living primary cell cultures from hippocampus, a key memory area in the brain.
Results are contained in 14 published, and 2 submitted papers, and 3 manuscripts. To study when and where in the brain the Nogo genes are active we localized and quantified RNA species (RNA is the product of DNA that codes for proteins) from birth to old age. Interestingly, levels of key Nogo signaling genes are upheld in aged mice. However, the expression of 11 key Nogo genes becomes altered by strong stimulation with a temporo-spatial pattern of orderly transcriptional regulations that strengthen the role of Nogo-signaling for synaptic plasticity. The largest alterations occur in the dentate gyrus, and the CA1 region of hippocampus. Changes occurred somewhat later in the cerebral cortex. We revealed that different gene alterations combine to decrease Nogo-like signaling and allow structural plasticity responses. Other genes were altered in the opposite direction, suggesting that the brain prepares in advance in order to rapidly restore balance. We find impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice, suggesting that NgR1-regulated synaptic plasticity is needed to develop stereotypies. NgR1 overexpression resulted in reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. We show that NgR1 is a negative regulator of structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.
Cell cultures revealed precise location of NgR1 in the presynaptic part of synapses, and we have preliminary GROUND-BREAKING results suggesting that down-regulation of NgR1 is mediated by metabotrophic effects of NMDA receptor activation. Confirmed, this would open a major novel target area for the treatment of memory failure. NgR1 regulation is driven by local activated nerve cells, while DA contributes global plasticity signals. We have discovered that increased NgR1 levels strongly inhibits DA release in the same area. These preliminary data points to a second GROUND-BREAKING finding coupling global and local control of memory formation. We intend to follow this up in our Parkinson model and hypothesize that high NgR1 not only inhibits DA release, but that also low DA levels may impair down-regulation of NgR1.

Reported by

KAROLINSKA INSTITUTET
Sweden
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