title: Activity-induced and developmental downregulation of the Nogo receptor.
abstract: The three axon growth inhibitory proteins, myelin associated glycoprotein, oligodendrocyte-myelin glycoprotein and Nogo-A, can all bind to the Nogo-66 receptor (NgR). This receptor is expressed by neurons with high amounts in regions of high plasticity where Nogo expression is also high. We hypothesized that simultaneous presence of high levels of Nogo and its receptor in neurons confers a locked state to hippocampal and cortical microcircuitry and that one or both of these proteins must be effectively and temporarily downregulated to permit plastic structural changes underlying formation of long-term memory. Hence, we subjected rats to kainic acid treatment and exposed rats to running wheels and measured NgR mRNA levels by quantitative in situ hybridization at different time points. We also studied spinal cord injuries and quantified NgR mRNA levels in spinal cord and ganglia during a critical postnatal period using real-time PCR. Strikingly, kainic acid led to a strong transient downregulation of NgR mRNA levels in gyrus dentatus, hippocampus, and neocortex during a time when BDNF mRNA was upregulated instead. Animals exposed to running wheels for 3 and 7, but not 1 or 21, days showed a significant downregulation of NgR mRNA in cortex, hippocampus and the dentate gyrus. NgR mRNA levels decreased from high to low expression in spinal cord and ganglia during the first week of life. No robust regulation of NgR was observed in the spinal cord following spinal cord injury. Together, our data show that NgR levels in developing and adult neurons are regulated in vivo under different conditions. Strong, rapid and transient downregulation of NgR mRNA in response to kainic acid and after wheel running in cortex and hippocampus suggests a role for NgR and Nogo-A in plasticity, learning and memory.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 17177, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Josephson
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trifunovski
authors.forename: Camilla
authors.initials: C
authors.lastname: Schéele
authors.forename: Johan
authors.initials: J
authors.lastname: Widenfalk
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Stefan
authors.initials: S
authors.lastname: Brené
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Christian
authors.initials: C
authors.lastname: Spenger
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006613:Higher Nervous Activity / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D007858:Learning / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009185:Myelin Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000235:genetics*; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C000603197:Rtn4 protein, rat; C486581:Rtn4r protein, rat; D007608:Kainic Acid