Neuritin Mediates Nerve Growth Factor–Induced Axonal Regeneration and Is Deficient in Experimental Diabetic Neuropathy

Karamoysoyli, Eugenia; Burnand, Rebecca C.; Tomlinson, David R.; Gardiner, Natalie J.

doi:10.2337/db07-0895

Cited by 78 publications

(55 citation statements)

References 54 publications

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“…The mechanisms underlying the regulation of neuritin are unclear, but neuritin expression is regulated by pathways that mediate neuronal plasticity, including induction of BDNF expression and signaling (9), and are decreased by stress and increased by antidepressant treatment (19,24). Neuritin is enriched in synapses (10,11), and increased expression could underlie the enhanced synaptic plasticity and dendrite morphology reported for antidepressants (24,34). The induction of spine density and dendrite branching in response to increased neuritin expression is consistent with this hypothesis.…”

Section: Discussionsupporting

confidence: 75%

“…These effects may be related to the role of neuritin in neurite outgrowth (9)(10)(11)(12)(13) and spine formation (present study), which could facilitate synaptic plasticity. The ability of neuritin to enhance memory in these models is consistent with the hypothesis that the actions of antidepressant treatment are mediated by increasing neural plasticity (6,31).…”

Section: Discussionmentioning

confidence: 99%

“…Neuritin, also known as candidate plasticity gene 15 (CPG15), encodes a small, extracellular GPI-anchored protein critical for dendritic outgrowth, maturation, and axonal regeneration (9)(10)(11)(12)(13). Neuritin expression in the hippocampus is induced by neuronal activity following chemical-or electrical-induced seizures (9,14,15), ischemia (16), and exercise (5,17).…”

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confidence: 99%

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Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress

Son

Banasr

Choi³

et al. 2012

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

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Decreased neuronal dendrite branching and plasticity of the hippocampus, a limbic structure implicated in mood disorders, is thought to contribute to the symptoms of depression. However, the mechanisms underlying this effect, as well as the actions of antidepressant treatment, remain poorly characterized. Here, we show that hippocampal expression of neuritin, an activity-dependent gene that regulates neuronal plasticity, is decreased by chronic unpredictable stress (CUS) and that antidepressant treatment reverses this effect. We also show that viral-mediated expression of neuritin in the hippocampus produces antidepressant actions and prevents the atrophy of dendrites and spines, as well as depressive and anxiety behaviors caused by CUS. Conversely, neuritin knockdown produces depressive-like behaviors, similar to CUS exposure. The ability of neuritin to increase neuroplasticity is confirmed in models of learning and memory. Our results reveal a unique action of neuritin in models of stress and depression, and demonstrate a role for neuroplasticity in antidepressant treatment response and related behaviors.is a devastating and recurrent illness affecting up to 17% of the population, resulting in personal disability, increased rates of suicide, and socioeconomic loss (1). Moreover, currently available antidepressants are only effective in approximately one-third of patients with MDD and in up to two-thirds after multiple trials, and they take weeks to months to produce a response (2, 3). In addition, the mechanisms underlying the therapeutic actions of antidepressants are poorly understood. New targets beyond monoamine signaling are now emerging in both preclinical and clinical reports of MDD (4, 5). These studies have focused on key limbic brain structures, including the hippocampus, that are significantly altered by chronic stress and depression and that are known to regulate mood, anxiety, and cognition (6, 7). Hippocampal synaptic plasticity has received much attention in recent years because human imaging and rodent studies demonstrate that stress and depression are associated with decreased hippocampal volume and atrophy of neurons (6,8).Neuritin, also known as candidate plasticity gene 15 (CPG15), encodes a small, extracellular GPI-anchored protein critical for dendritic outgrowth, maturation, and axonal regeneration (9-13). Neuritin expression in the hippocampus is induced by neuronal activity following chemical-or electrical-induced seizures (9, 14, 15), ischemia (16), and exercise (5, 17). Neuritin has been implicated in the actions of BDNF (9, 18), which is up-regulated in the hippocampus by antidepressant treatment and is sufficient to produce antidepressant behavioral responses (19,20). Moreover, chronic antidepressant treatment has been shown to increase neuritin expression in rat brain (21). The current study was conducted to test the hypothesis that neuritin is a critical downstream mediator of antidepressant/BDNF-mediated plasticity and, conversely, that loss of neuritin could contribute to depre...

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress

Son

Banasr

Choi³

et al. 2012

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

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“…NRN1 continues to be expressed in the adult brain, where its expression is correlated with activity-dependent functional synaptic plasticity (Corriveau et al 1999;Harwell et al 2005;Flavell and Greenberg 2008). Furthermore, the expression of NRN1 is regulated by neurotrophins such as brain-derived neurotrophic factor (BDNF, 11p13) (Naeve et al 1997;Karamoysoyli et al 2008). BDNF promotes the differentiation and growth of developing neurons in central and peripheral nervous systems (Buckley et al 2007) and its intracellular distribution and activity-dependent secretion is altered by the Met variant of a functional polymorphism in the BDNF gene, which consists of a valine (Val) substitution for methionine (Met) at codon 66 (Val66Met).…”

Section: Introductionmentioning

confidence: 99%

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

Fatjó‐Vilas

Prats

Pomarol‐Clotet

et al. 2015

The World Journal of Biological Psychiatry

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Objectives: Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods: The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results: The frequency of the haplotype C-C (rs645649-rs582262) was significantly increased in patients compared to controls (P ¼ 0.0043), while the haplotype T-C-C-T-C-A (rs3763180-rs10484320-rs4960155-rs9379002-rs9405890-rs1475157) was more frequent in controls (P ¼ 3.1 Â 10 À5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P ¼ 0.005). Conclusions: Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF. ARTICLE HISTORY

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“…Differential gene-expression analysis revealed the down-regulation of many genes with DMI treatment after SNI in Rgs9KO mice compared with wild-type controls, including Adcyap1 and Bdnf, for which reduced function is associated with reduced neuropathic pain sensitivity (28,29), and Adcy1, the deletion of which reduces mechanical allodynia and inflammatory pain sensitivity (41). The expression of regulator of neurite outgrowth neuritin 1 (Nrn1), a gene that is stimulated by Bdnf and is implicated in antidepressant actions (42,43) and diabetic neuropathy (44), is also altered. Several other genes with documented roles in chronic pain and antidepressant actions that are down-regulated by chronic DMI treatment in the Rgs9KO SNI group, including Neuropeptide Y1 receptor (Npy1R) (Fig.…”

Section: Discussionmentioning

confidence: 99%

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

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

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The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

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Neuritin Mediates Nerve Growth Factor–Induced Axonal Regeneration and Is Deficient in Experimental Diabetic Neuropathy

Cited by 78 publications

References 54 publications

Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress

Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

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