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Mild traumatic brain injury (mTBI) constitutes 75 ∼ 90% of all TBI cases and causes various physical, cognitive, emotional, and other psychological symptoms. Nogo receptor 1 (NgR1) is a regulator of structural brain plasticity during development and in adulthood. Here, we used mice that, in the absence of doxycycline, overexpress NgR1 in forebrain neurons (MemoFlex) to determine the role of NgR1 in recovery from mTBI with respect to balance, cognition, memory, and emotion. We compared wild-type (WT), MemoFlex, and MemoFlex + doxycycline mice to the same three groups subjected to mTBI. mTBI was induced by a controlled 30-g weight drop. We found that inability to downregulate NgR1 significantly impairs recovery from mTBI-induced impairments. When the NgR1 transgene was turned off, recovery was similar to that of WT mice. The results suggest that the ability to regulate NgR1 signaling is needed for optimal recovery of motor coordination and balance, spatial memory, cognition, and emotional functions after mTBI.

In the search for molecules that may alter the formation of amyloid-β (Aβ) protofibrils, it has been shown that the Nogo-system can interact and bind to amyloid-β protein precursor and thus affect the amount of Aβ that is formed and deposited in the brain. To further address this issue in vivo, we crossed mice that overexpress Nogo receptor 1 (NgR1), "MemoFlex", in forebrain neurons, with plaque forming APPswe/PSEN1(ΔE9) mice, to investigate if increased levels of NgR1 would influence plaque load or cognitive function in the resulting MemoFlex/APPswe/PSEN1(ΔE9) transgenic mice. We used a radial arm water maze and the Morris water maze to measure cognitive function. We did not find any significant effect of NgR1 overexpression on the performance of APPswe/PSEN1(ΔE9) mice in the radial arm water maze test. However, MemoFlex/APPswe/PSEN1(ΔE9) mice were found to be significantly impaired in the Morris water maze. We also analyzed the amount of plaques in the two mouse models without finding any significant difference in plaque load in the cerebral cortex or the hippocampal formation. It therefore appears that overexpression of NgR1 in APPswe/PSEN1(ΔE9) mice does not have any marked effects on Aβ levels, yet appears to impair spatial cognitive abilities. We conclude that strong overexpression of NgR1 in forebrain neurons impairs aspects of cognitive function but does not markedly alter plaque load in plaque-forming APPswe/PSEN1(ΔE9) mice. Thus high levels of membrane-bound NgR1 present since early postnatal life does not influence the development of plaques in mice carrying the two human plaque-causing mutations APPswe and PSEN1(ΔE9).

Nogo Receptor 1 (NgR1) mRNA is downregulated in hippocampal and cortical regions by increased neuronal activity such as a kainic acid challenge or by exposing rats to running wheels. Plastic changes in cerebral cortex in response to loss of specific sensory inputs caused by spinal cord injury are also associated with downregulation of NgR1 mRNA. Here we investigate the possible regulation by neuronal activity of the homologous receptors NgR2 and NgR3 as well as the endogenous NgR1 antagonist LOTUS and the ligand Nogo. The investigated genes respond to kainic acid by gene-specific, concerted alterations of transcript levels, suggesting a role in the regulation of synaptic plasticity, Downregulation of NgR1, coupled to upregulation of the NgR1 antagonist LOTUS, paired with upregulation of NgR2 and 3 in the dentate gyrus suggest a temporary decrease of Nogo/OMgp sensitivity while CSPG and MAG sensitivity could remain. It is suggested that these activity-synchronized temporary alterations may serve to allow structural alterations at the level of local synaptic circuitry in gray matter, while maintaining white matter pathways and that subsequent upregulation of Nogo-A and NgR1 transcript levels signals the end of such a temporarily opened window of plasticity. [ABSTRACT FROM AUTHOR]