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

Abstract

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...

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

“…Consistent with the rapid antidepressant effects of ketamine in intact animals (4), ketamine produced similar behavioral responses in rats infused with lenti-GFP control virus in the novelty suppressed feeding test (NSFT) (22), the forced swim test (FST), and the learned helplessness test (LHT), assays of anxiety (NFST) and despair (FST and LHT) that are responsive to antidepressant treatments (4,22) (Fig. 4).…”

“…We next determined whether systemic ketamine administration at a low dose (10 mg/kg) that is reported to have antidepressant actions (4), also induces HDAC5 phosphorylation in the hippocampus, a region that contributes to antidepressant behavioral responses (22) and that is reduced in volume in patients with MDD (23). Ketamine injection transiently increased HDAC5 phosphorylation at both S259 and S498; the increase was significant at 30 min, maximal (approximately fourfold) after 6 h and still elevated at longer time points (12-24 h) (Fig.…”

“…Lentiviral Production. For HDAC5 knockdown, we cloned a shRNA sequence against HDAC5 (31) into pll3.7 (Addgene) and used a control nontargeting shRNA (22). Lentivirus was produced as indicated in SI Appendix.…”

“…Primary hippocampal neurons were prepared from 16.5-d-old Sprague-Dawley rat embryos, as previously described (22).…”

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

“…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.…”