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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"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. "
[Show abstract][Hide abstract] 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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Early temporary windows of heightened brain plasticity called critical periods developmentally sculpt neural circuits and contribute to adult behavior. Regulatory mechanisms of visual cortex development - the preeminent model of experience-dependent critical period plasticity-actively limit adult plasticity and have proved fruitful therapeutic targets to reopen plasticity and rewire faulty visual system connections later in life. Interestingly, these molecular mechanisms have been implicated in the regulation of plasticity in other functions beyond vision. Applying mechanistic understandings of critical period plasticity in the visual cortex to fear circuitry may provide a conceptual framework for developing novel therapeutic tools to mitigate aberrant fear responses in post traumatic stress disorder. In this review, we turn to the model of experience-dependent visual plasticity to provide novel insights for the mechanisms regulating plasticity in the fear system. Fear circuitry, particularly fear memory erasure, also undergoes age-related changes in experience-dependent plasticity. We consider the contributions of molecular brakes that halt visual critical period plasticity to circuitry underlying fear memory erasure. A major molecular brake in the visual cortex, perineuronal net formation, recently has been identified in the development of fear systems that are resilient to fear memory erasure. The roles of other molecular brakes, myelin-related Nogo receptor signaling and Lynx family proteins - endogenous inhibitors for nicotinic acetylcholine receptor, are explored in the context of fear memory plasticity. Such fear plasticity regulators, including epigenetic effects, provide promising targets for therapeutic interventions.
Frontiers in Psychiatry 11/2013; 4:146. DOI:10.3389/fpsyt.2013.00146
"These molecules bind to members of the Nogo receptor (NgR) family, which regulate dendritic spine shape and play a critical role in limiting the formation of new synapses in post-synaptic neurons (Lee et al. 2008; Wills et al. 2012). Furthermore, expression of NgR family members is down-regulated by neuronal activity and this may play a role in facilitating activity-dependent synapse development and in regulating anatomical plasticity in the adult (Wills et al. 2012; Akbik et al. 2013). Genetic deletion experiments have also demonstrated that the Nogo-NgR axis contributes to closure of the critical period of ocular dominance plasticity (McGee et al. 2005). "
[Show abstract][Hide abstract] ABSTRACT: During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. This article is protected by copyright. All rights reserved.
Journal of Neurochemistry 10/2013; 129(2). DOI:10.1111/jnc.12502 · 4.28 Impact Factor