Activity-induced and developmental downregulation of the Nogo receptor

TY - JOUR

T1 - Activity-induced and developmental downregulation of the Nogo receptor

AU - Josephson, Anna

AU - Trifunovski, Alexandra

AU - Schéele, Camilla

AU - Widenfalk, Johan

AU - Wahlestedt, Claes

AU - Brené, Stefan

AU - Olson, Lars

AU - Spenger, Christian

PY - 2003/3

Y1 - 2003/3

N2 - 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.

AB - 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.

KW - Animals

KW - Brain

KW - Brain-Derived Neurotrophic Factor

KW - Cerebral Cortex

KW - Disease Models, Animal

KW - Down-Regulation

KW - GPI-Linked Proteins

KW - Ganglia, Spinal

KW - Higher Nervous Activity

KW - Hippocampus

KW - Kainic Acid

KW - Learning

KW - Male

KW - Motor Activity

KW - Myelin Proteins

KW - Neuronal Plasticity

KW - Nogo Proteins

KW - Nogo Receptor 1

KW - RNA, Messenger

KW - Rats

KW - Rats, Inbred SHR

KW - Rats, Sprague-Dawley

KW - Receptors, Cell Surface

KW - Receptors, Peptide

KW - Spinal Cord

KW - Spinal Cord Injuries

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s00441-002-0695-8

DO - 10.1007/s00441-002-0695-8

M3 - Journal article

C2 - 12658441

SN - 0302-766X

VL - 311

SP - 333

EP - 342

JO - Cell and Tissue Research

JF - Cell and Tissue Research

IS - 3

ER -