ABSTRACT
Experience can shape cortical circuits, especially during critical periods for plasticity. In visual cortex, imbalance of activity from the two eyes during the critical period shifts ocular dominance (OD) towards the more active eye. Inhibitory circuits are crucial in this process: OD plasticity is absent in GAD65KO mice that show diminished inhibition. This defect can be rescued by application of benzodiazepines, which increase GABAergic signalling. However, it is unknown how such changes in inhibition might disrupt and then restore OD plasticity. Since NMDA dependent synaptic plasticity mechanisms are also known to contribute to OD plasticity, we investigated whether NMDA receptor levels and function are also altered in GAD65KO. There are reduced NR2A levels and slower NMDA currents in visual cortex of GAD65KO mice. Application of benzodiazepines, which rescues OD plasticity, also increases NR2A levels. Thus it appears as if OD plasticity can be restored by adding a critical amount of excitatory transmission through NR2A-containing NMDA receptors. Together, these observations can unify competing ideas of how OD plasticity is regulated: changes in either inhibition or excitation would engage homeostatic mechanisms that converge to regulate NMDA receptors, thereby enabling plasticity mechanisms and also ensuring circuit stability.
Subject(s)
Dominance, Ocular/physiology , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/physiology , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/physiology , Animals , Blotting, Western , Densitometry , Diazepam/pharmacology , Electrophysiology , GABA Modulators/pharmacology , In Situ Hybridization , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/genetics , Neuronal Plasticity/physiology , Receptors, GABA/physiology , Reverse Transcriptase Polymerase Chain Reaction , Visual Cortex/physiologyABSTRACT
Experience can alter synaptic connectivity throughout life, but the degree of plasticity present at each age is regulated by mechanisms that remain largely unknown. Here, we demonstrate that Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, is expressed in subsets of neurons throughout the brain. Neuronal PirB protein is associated with synapses and forms complexes with the phosphatases Shp-1 and Shp-2. Soluble PirB fusion protein binds to cortical neurons in an MHCI-dependent manner. In mutant mice lacking functional PirB, cortical ocular-dominance plasticity is more robust at all ages. Thus, an MHCI receptor is expressed in central nervous system neurons and functions to limit the extent of experience-dependent plasticity in the visual cortex throughout life. PirB is also expressed in many other regions of the central nervous system, suggesting that it may function broadly to stabilize neural circuits.
Subject(s)
Dominance, Ocular/physiology , Neuronal Plasticity , Receptors, Immunologic/physiology , Synapses/physiology , Visual Cortex/physiology , Aging , Animals , Brain/metabolism , Cells, Cultured , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Histocompatibility Antigens Class I/metabolism , In Situ Hybridization , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred C57BL , Mutation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Phosphorylation , Protein Binding , Protein Structure, Tertiary , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Protein Tyrosine Phosphatases/metabolism , Receptors, Immunologic/chemistry , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Recombinant Fusion Proteins/metabolism , Synapses/metabolismABSTRACT
Pathophysiologic hypotheses for Alzheimer's disease (AD) are centered on the role of the amyloid plaque Abeta peptide and the mechanism of its derivation from the amyloid precursor protein (APP). As part of the disease process, an aberrant axonal sprouting response is known to occur near Abeta deposits. A Nogo to Nogo-66 receptor (NgR) pathway contributes to determining the ability of adult CNS axons to extend after traumatic injuries. Here, we consider the potential role of NgR mechanisms in AD. Both Nogo and NgR are mislocalized in AD brain samples. APP physically associates with the NgR. Overexpression of NgR decreases Abeta production in neuroblastoma culture, and targeted disruption of NgR expression increases transgenic mouse brain Abeta levels, Abeta plaque deposition, and dystrophic neurites. Infusion of a soluble NgR fragment reduces Abeta levels, amyloid plaque deposits, and dystrophic neurites in a mouse transgenic AD model. Changes in NgR level produce parallel changes in secreted APPalpha and Abeta, implicating NgR as a blocker of secretase processing of APP. The NgR provides a novel site for modifying the course of AD and highlights the role of axonal dysfunction in the disease.
Subject(s)
Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Myelin Proteins/metabolism , Plaque, Amyloid/metabolism , Receptors, Cell Surface/metabolism , Alzheimer Disease/metabolism , Animals , Brain Chemistry , Cell Line , GPI-Linked Proteins , Humans , Mice , Mice, Knockout , Mice, Transgenic , Myelin Proteins/analysis , Myelin Proteins/genetics , Nogo Proteins , Nogo Receptor 1 , Rats , Receptors, Cell Surface/analysis , Receptors, Cell Surface/geneticsABSTRACT
After injury, axons of the adult mammalian brain and spinal cord exhibit little regeneration. It has been suggested that axon growth inhibitors, such as myelin-derived Nogo, prevent CNS axon repair. To investigate this hypothesis, we analyzed mice with a nogo mutation that eliminates Nogo-A/B expression. These mice are viable and exhibit normal locomotion. Corticospinal tract tracing reveals no abnormality in uninjured nogo-A/B(-/-) mice. After spinal cord injury, corticospinal axons of young adult nogo-A/B(-/-) mice sprout extensively rostral to a transection. Numerous fibers regenerate into distal cord segments of nogo-A/B(-/-) mice. Recovery of locomotor function is improved in these mice. Thus, Nogo-A plays a role in restricting axonal sprouting in the young adult CNS after injury.
Subject(s)
Axons/physiology , Myelin Proteins/deficiency , Nerve Regeneration , Animals , Axotomy , Brain/cytology , Female , Fetal Viability/genetics , Male , Mice , Mice, Knockout , Motor Activity/physiology , Myelin Proteins/genetics , Myelin Sheath/physiology , Nerve Regeneration/genetics , Nerve Regeneration/physiology , Nogo Proteins , Phenotype , Pyramidal Tracts/cytology , Pyramidal Tracts/pathology , Recovery of Function/genetics , Spatial Behavior/physiology , Spinal Cord Injuries/genetics , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathologyABSTRACT
Nogo has been identified as a component of central nervous system (CNS) myelin preventing axonal regeneration in the adult vertebrate CNS. Our previous analysis of Nogo-A demonstrated that an axon-inhibiting 66 aa domain is expressed at the extracellular surface and the endoplasmic reticulum lumen of transfected cells and oligodendrocytes. We have identified a brain-specific, leucine-rich repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. With identified ligand and receptor components, structure-function determinants for inhibition of axon regeneration can now be mapped. The relative contribution of Nogo, myelin-associated glycoprotein, chondroitin sulfate proteoglycan and oligodendrocyte myelin glycoprotein to myelin inhibition can be assessed. Blockade of Nogo-66 interaction with its receptor provides one potential avenue to promote axonal regeneration after adult mammalian CNS injury.
Subject(s)
Growth Inhibitors/physiology , Myelin Proteins/physiology , Nerve Regeneration/physiology , Receptors, Cell Surface/physiology , Animals , Axons/physiology , GPI-Linked Proteins , Humans , Myelin Sheath/physiology , Nogo Proteins , Nogo Receptor 1 , Signal TransductionABSTRACT
Axonal regeneration in the adult central nervous system (CNS) is limited by two proteins in myelin, Nogo and myelin-associated glycoprotein (MAG). The receptor for Nogo (NgR) has been identified as an axonal glycosyl-phosphatidyl-inositol (GPI)-anchored protein, whereas the MAG receptor has remained elusive. Here, we show that MAG binds directly, with high affinity, to NgR. Cleavage of GPI-linked proteins from axons protects growth cones from MAG-induced collapse, and dominant-negative NgR eliminates MAG inhibition of neurite outgrowth. MAG-resistant embryonic neurons are rendered MAG-sensitive by expression of NgR. MAG and Nogo-66 activate NgR independently and serve as redundant NgR ligands that may limit axonal regeneration after CNS injury.
Subject(s)
Axons/physiology , Myelin-Associated Glycoprotein/metabolism , Neurites/physiology , Receptors, Cell Surface/metabolism , Animals , Binding Sites , COS Cells , Chick Embryo , Cloning, Molecular , GPI-Linked Proteins , Ganglia, Spinal/cytology , Ganglia, Spinal/embryology , Ganglia, Spinal/metabolism , Gene Library , Ligands , Mice , Myelin Proteins/chemistry , Myelin Proteins/metabolism , Myelin Proteins/pharmacology , Myelin-Associated Glycoprotein/chemistry , Myelin-Associated Glycoprotein/genetics , Nerve Regeneration , Neurons/metabolism , Nogo Proteins , Nogo Receptor 1 , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Phosphatidylinositol Diacylglycerol-Lyase , Protein Structure, Tertiary , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/genetics , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Sialic Acids/metabolism , Transfection , Type C Phospholipases/metabolismABSTRACT
Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1 40) antagonist peptide (NEP1 40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1 40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.
