Nogo receptor 1 regulates formation of lasting memories

Karlén, Alexandra; Karlsson, Tobias E.; Mattsson, Anna; Lundströmer, Karin; Codeluppi, Simone; Pham, T. M.; Bäckman, Cristina M.; Ögren, Sven Ove; Åberg, Elin; Hoffman, Alexander F.; Sherling, Michael A.; Lupica, Carl R.; Hoffer, Barry J.; Spenger, Christian; Josephson, Anna; Brené, Stefan; Olson, Lar̀s

doi:10.1073/pnas.0905390106

Cited by 75 publications

(92 citation statements)

References 46 publications

(43 reference statements)

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“…This is a phenomenon that is frequently observed when comparing acute interventions with constitutive KOs where compensatory mechanisms are often activated. These results are also in line with the proposed role of NogoA and NgR1 in regulating the stabilization of neuronal circuits and in inhibiting structural rearrangements and thereby limiting, e.g., spinal cord, or ocular dominance (OD) plasticity (9,27,30,31), or regulating the formation of long-lasting memories (15).…”

Section: Discussionsupporting

confidence: 72%

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NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

Delekate

Zagrebelsky²,

Kramer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

114

116

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Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (longterm potentiation, LTP) in the presence of function blocking antiNogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short-term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA A receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks.C hanges in the connectivity of neurons-synaptic plasticityregulate the fine-tuning of neuronal networks during development and during adult learning. Synaptic plasticity includes functional and structural modifications at neurons and may be the underlying mechanism for learning and memory processes (1). The storage of new information therefore might depend on ever changing neuronal networks. On the other hand, recent data indicate that the large scale organization of neuronal networks is kept remarkably stable to maintain a constant flow of information and to support long-term memory storage (reviewed in ref. 2).In the CA1 region of the hippocampus, changes in neuronal activity can lead to changes in synaptic weight. Molecular mechanisms include here changes in the number or properties of neurotransmitter receptors, retrograde messengers, structural changes at synapses, and activation of transcription/translation (3). What is less clear is whether molecular mechanisms restricting changes in synaptic weight and thus stabilizing the synapse also play a role as well. In this context it is interesting to note that preventing further potentiation of a given set of synapses in a neuronal network can be induced by a homeostatic shutdown of long-term potentiation (LTP) after intense stimulation (4). In the search for such molecular stabilizers, we investigated the protein NogoA, which has been identified as a negative regulator of structural changes in the CNS (5). NogoA prevents neurite outgrowth in the adult CNS after injury (6) and regulates the progressive restriction of plasticity dur...

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Section: Discussionsupporting

confidence: 72%

“…In ngr1 knockout (9) and in pirB knockout mice (13), ocular dominance plasticity continues after the end of the critical period, suggesting that NgR1 and PirB signaling stabilizes the neural circuitry and limits experience-dependent plasticity. In addition, NgR1 signaling can influence LTP in concert with FGF2 (14) as well as long-term memory (15).…”

mentioning

confidence: 99%

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

Delekate

Zagrebelsky²,

Kramer³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

114

116

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“…Additionally, downregulation of NgR1 occurs during learning, and is suggested to be required for the formation of long-term memory ( Josephson et al, 2003). Inducible overexpression of NgR1 in forebrain neurons was also recently shown to be associated with impaired long-term memory, implying a complex role for NgR1 in memory consolidation (Karlen et al, 2009). Neither NgR1 deletion nor sNgR1 treatment impaired memory function in naive or sham-injured mice in our studies, although we cannot exclude the possibility that other, more complex tests could have revealed subtle deficits in cognitive function induced by the absence of NgR1.…”

Section: Nogo-66 Receptor Inhibition After Tbi In Micecontrasting

confidence: 47%

Genetic Deletion and Pharmacological Inhibition of Nogo-66 Receptor Impairs Cognitive Outcome after Traumatic Brain Injury in Mice

Hånell

Clausen

Björk

et al. 2010

Journal of Neurotrauma

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Functional recovery is markedly restricted following traumatic brain injury (TBI), partly due to myelin-associated inhibitors including Nogo-A, myelin-associated glycoprotein ( MAG) and oligodendrocyte myelin glycoprotein (OMgp), that all bind to the Nogo-66 receptor-1 (NgR1). In previous studies, pharmacological neutralization of both Nogo-A and MAG improved outcome following TBI in the rat, and neutralization of NgR1 improved outcome following spinal cord injury and stroke in rodent models. However, the behavioral and histological effects of NgR1 inhibition have not previously been evaluated in TBI. We hypothesized that NgR1 negatively influences behavioral recovery following TBI, and evaluated NgR1 À/À mice (NgR1 À/À study) and, in a separate study, soluble NgR1 infused intracerebroventricularly immediately post-injury to neutralize NgR1 (sNgR1 study) following TBI in mice using a controlled cortical impact (CCI) injury model. In both studies, motor function, TBI-induced loss of tissue, and hippocampal b-amyloid immunohistochemistry were not altered up to 5 weeks post-injury. Surprisingly, cognitive function (as evaluated with the Morris water maze at 4 weeks post-injury) was significantly impaired both in NgR1 À/À mice and in mice treated with soluble NgR1. In the sNgR1 study, we evaluated hippocampal mossy fiber sprouting using the Timm stain and found it to be increased at 5 weeks following TBI. Neutralization of NgR1 significantly increased mossy fiber sprouting in sham-injured animals, but not in brain-injured animals. Our data suggest a complex role for myelin-associated inhibitors in the behavioral recovery process following TBI, and urge caution when inhibiting NgR1 in the early post-injury period.

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“…(McGee et al, 2005). Interestingly, a recent study has demonstrated that NgR1 is required for lasting memories (Karlén et al, 2009). Given that LGI1 is critically important for glutamatergic synapse maturation and dendritic pruning (Zhou et al, 2009), determining whether LGI1, NgR1 and ADAM22 function collaboratively to drive synapse maturation and dendritic sculpting is a key priority for future studies.…”

Section: Discussionmentioning

confidence: 99%

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

Thomas

Favell²,

Morante‐Redolat³

et al. 2010

J. Neurosci.

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Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features.LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.

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Nogo receptor 1 regulates formation of lasting memories

Cited by 75 publications

References 46 publications

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

Genetic Deletion and Pharmacological Inhibition of Nogo-66 Receptor Impairs Cognitive Outcome after Traumatic Brain Injury in Mice

LGI1 Is a Nogo Receptor 1 Ligand that Antagonizes Myelin-Based Growth Inhibition

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