Abstract
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.
Highlights
Structural synaptic plasticity in the central nervous system is under tight control, and partly mediated by the Nogo signaling system [1,2,3]
Nogo Receptor 1 (NgR1) mRNA is Downregulated by Kaninic Acid We have previously shown in rats and mice that NgR1 is rapidly downregulated after kainic acid injections [22,25]
Areaspecific downregulation of NgR1 mRNA occurs in those hind limb and neighboring forelimb somatosensory cortical areas that undergo functional plastic alterations following spinal cord injury in rats [21]
Summary
Structural synaptic plasticity in the central nervous system is under tight control, and partly mediated by the Nogo signaling system [1,2,3]. The inhibitory protein was cloned and named Nogo [6,7,8], and it was shown that Nogo had three different isoforms, A, B and C. Identified co-receptors include p75 [10], Troy [11,12] and Lingo-1 [13] and through combinations of these co-receptors Nogo-NgR1 signaling can result in activation of RhoA [14]. NgR1 is expressed by neurons and downregulated in several different situations associated with increased neuronal activity and plasticity [21,22,23]. MAG has been found to bind to NgR2 but not to NgR3; neither Nogo-A nor OMgp has been reported to bind to these homologous receptors [27]. In the search for molecules that would affect the growth of the lateral olfactory tract, a protein named LOTUS was found and shown to be an endogenous antagonist of NgR1, able to compete with Nogo-A for NgR1 [29]
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