A single link to the first track to allow the export script to build the search page
  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    153—Mood Disorders: Human Postmortem Studies

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    153.05: NRG1-ErbB signaling in affective regulation and antidepressant efficacy in suicide and depression

    Location: Halls B-H

    *I. MAHAR1,2, B. LABONTE1,2, J. P. LOPEZ1,3, G. TURECKI1,2,3,4, N. MECHAWAR1,2,4;
    1McGill Group for Suicide Studies, Douglas Mental Hlth. Univ. Inst., Montreal, QC, Canada; 2Neurosci., 3Human Genet., 4Psychiatry, McGill Univ., Montreal, QC, Canada

    Abstract Body: Background 
    Hippocampal neurogenesis has been implicated in the mechanism of antidepressant (AD) action. We have shown (Mahar et al, 2011, PLoS ONE 6: e26610) that peripheral subchronic NRG1β administration in mice selectively increases cell proliferation and neurogenesis in the caudal dentate gyrus within the ventral hippocampus, and that this effect may be mediated by ErbB3 receptors, which are expressed by newborn cells from division to maturity and colocalize with SOX2 in the subgranular zone. In addition, four weeks after cessation of subchronic treatment, animals display robust AD-like behavior, whereas acute treatment does not affect behavior. To extend these findings, we are currently investigating whether NRG1-ErbB signaling is related to psychiatric illness and response to AD treatment. We hypothesized that hippocampal ErbB3 expression would be decreased in suicide completers, that NRG1 expression may be altered with psychiatric and medication status, and that peripheral NRG1 expression may be related to AD response.
    Methods
    To examine peripheral expression of NRG1, blood was obtained from depressed patients before (T0) and after eight weeks of AD treatment (T8) as described previously (Lopez et al, 2013, Mol Psych 18:398-9). Subjects completed the Hamilton Depression Rating Scale. To examine central expression, post-mortem hippocampal samples were obtained from the Douglas - Bell Canada Brain Bank from suicide completers and controls. Expression was quantified by RT-PCR normalized to endogenous housekeeping genes.
    Results
    Peripheral NRG1 expression (at T0) correlated with depressive symptom recovery (T8), with AD medication-responders tending to have higher blood NRG1 expression than non-responders pre-treatment. We are currently increasing sample size as well as adding control samples to extend this analysis. Hippocampal expression of ErbB3 (but not EGFR, ErbB2, ErbB4, or overall NRG1) was reduced in suicides, as reported previously (Mahar et al, 2011, SfN Annual Meeting 902.88), whereas expression of NRG1β isoforms was significantly increased for suicides who had received AD medication compared to controls, but did not differ between controls and suicides without AD treatment. 
    Conclusions
    These preliminary results suggest that peripheral NRG1, previously associated with hippocampal neurogenesis and AD-like effects in animal studies, may be a biomarker for AD efficacy in depressed patients, and that hippocampal NRG1β increases with AD treatment, whereas suicides show reduced ErbB3 expression.
    Funding: CIHR, FRQS

    Lay Language Summary: Our research suggests that individuals that commit suicide may have lower expression of a gene implicated in both emotional behavior and the birth of new neurons, in a part of the brain involved in emotion and memory. Our study also indicates that depressed patients that have higher expression of a related gene in blood respond better to antidepressant treatment. Together these results highlight a potential new biological pathway involved in psychiatric illness and response to treatment.
    Suicide is a major social problem and leading cause of death worldwide. Suicidality is strongly associated with depressive illness, and the underlying biological causes of this illness remain misunderstood. Similarly, the identification in depressed patients of factors that could predispose to a better treatment response or increase the efficacy of antidepressants is one of the major challenges in the burgeoning field of molecular psychiatry.
    We have previously shown that the protein neuregulin-1 can cause antidepressant-like effects in animals and can increase the birth of new neurons in the hippocampus, a phenomenon associated with emotional behavior as well as response to antidepressants. In addition, we have shown that these effects are likely mediated by ErbB3, a receptor for neuregulin-1.
    In the present study, we looked at the brains of suicide completers and control subjects, and found that expression of the ErbB3 gene was decreased in the hippocampus of people who had committed suicide. These results suggest that although increased neuregulin-ErbB3 activity in the hippocampus has antidepressant effects, decreased activity is related to suicidality. We also measured the expression of the neuregulin-1 gene in the blood of depressed patients before and after treatment, and found that depressed patients who responded successfully to antidepressant treatment had higher expression of neuregulin-1 in their blood, suggesting that activity in this pathway might predict (or even mediate) the effectiveness of antidepressant medication.
    These results shed light on the complex roots of depression and suicide, and may thus lead to better targeted therapeutic and preventive interventions.