Anatomical Plasticity of Adult Brain Is Titrated by Nogo Receptor 1

Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, CT 06536, USA.
Neuron (Impact Factor: 15.05). 03/2013; 77(5):859-66. DOI: 10.1016/j.neuron.2012.12.027
Source: PubMed


Experience rearranges anatomical connectivity in the brain, but such plasticity is suppressed in adulthood. We examined the turnover of dendritic spines and axonal varicosities in the somatosensory cortex of mice lacking Nogo Receptor 1 (NgR1). Through adolescence, the anatomy and plasticity of ngr1 null mice are indistinguishable from control, but suppression of turnover after age 26 days fails to occur in ngr1-/- mice. Adolescent anatomical plasticity can be restored to 1-year-old mice by conditional deletion of ngr1. Suppression of anatomical dynamics by NgR1 is cell autonomous and is phenocopied by deletion of Nogo-A ligand. Whisker removal deprives the somatosensory cortex of experience-dependent input and reduces dendritic spine turnover in adult ngr1-/- mice to control levels, while an acutely enriched environment increases dendritic spine dynamics in control mice to the level of ngr1-/- mice in a standard environment. Thus, NgR1 determines the low set point for synaptic turnover in adult cerebral cortex.

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Available from: Stephen M Strittmatter, Aug 04, 2014
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    • "The analyses of secondary and tertiary dendrites in dorsal CA1 in NgR1 −/− mice have shown increased density of stubby spines at the expense of thin and mushroom spines (Lee et al. 2008), while there was no effect on total spine density. In the barrel cortex, neither spine density nor distribution of spine types was found to be affected by loss of NgR1 (Akbik et al. 2013). While the loss of NgR1 therefore does not appear to affect total spine density and to have different effects on spine types in different regions, we can now show that NgR1 overexpression in forebrain neurons results in robustly reduced total spine density and a reduction in mature mushroom spines in 3 out of 3 investigated brain areas. "
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    ABSTRACT: Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.
    Full-text · Article · Feb 2016 · Cerebral Cortex
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    • "In the adult system, a role for NgR1 in regulating synaptic turnover has been elucidated, but comparatively little is known about NgR2. NgR1 knockout resulted in a shift of spine morphologies in CA1 apical dendrites, with density of stubby spines increased and mushroom and thin spines decreased (Lee et al., 2008; Delekate et al., 2011), and recent work has shown that in the cortex, spine turnover in NgR1 knockout mice is significantly increased (Akbik et al., 2013). This implies regulation of spine motility by NgR1. "
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    ABSTRACT: Molecular mechanisms which stabilize dendrites and dendritic spines are essential for regulation of neuronal plasticity in development and adulthood. The class of Nogo receptor proteins, which are critical for restricting neurite outgrowth inhibition signaling, have been shown to have roles in developmental, experience and activity induced plasticity. Here we investigated the role of the Nogo receptor homolog NgR2 in structural plasticity in a transgenic null mutant for NgR2. Using Golgi-Cox staining to analyze morphology, we show that loss of NgR2 alters spine morphology in adult CA1 pyramidal neurons of the hippocampus, significantly increasing mushroom-type spines, without altering dendritic tree complexity. Furthermore, this shift is specific to apical dendrites in distal CA1 stratum radiatum (SR). Behavioral alterations in NgR2(-/-) mice were investigated using a battery of standardized tests and showed that whilst there were no alterations in learning and memory in NgR2(-/-) mice compared to littermate controls, NgR2(-/-) displayed reduced fear expression in the contextual conditioned fear test, and exhibited reduced anxiety- and depression-related behaviors. This suggests that the loss of NgR2 results in a specific phenotype of reduced emotionality. We conclude that NgR2 has role in maintenance of mature spines and may also regulate fear and anxiety-like behaviors.
    Full-text · Article · May 2014 · Frontiers in Behavioral Neuroscience
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    • "In a recent study, Nogo receptor knock-out mice were reported to show more pronounced fear extinction compared to wild type mice (37) (Figure 1B). At the dendritic spine level, fear extinction 3–4 days after fear conditioning involves spine growth on the same dendritic branches within 2 μm from the spines that were eliminated during conditioning in the cortex (38). "
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