Alteration in Kinase Activity But Not in Protein Levels of Protein Kinase B and Glycogen Synthase Kinase-3β in Ventral Prefrontal Cortex of Depressed Suicide Victims

Karege, Félicien; Perroud, Nader; Burkhardt, Sandra; Schwald, Michèle; Ballmann, Eladia; Harpe, R. La; Malafosse, Alain

doi:10.1016/j.biopsych.2006.04.036

Cited by 190 publications

(143 citation statements)

References 29 publications

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“…(v) An increase in GSK-3b activity was observed recently in patients with major depression in a postmortem study (Karege et al, 2007), and response to lithium augmentation in major depression was associated with the GSK-3b À50T/C single-nucleotide polymorphism (Adli et al, 2007).…”

Section: Glycogen Synthase Kinase-3 (Bipolar Disorder and Major Deprementioning

confidence: 84%

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Mathew

Manji

Charney

2008

Neuropsychopharmacol

206

140

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Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel therapies for unipolar depression and bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design therapeutics to attenuate or prevent those pathological processes. This review describes several promising drugs and drug targets for mood disorders using one or both of these approaches. Agents interacting with non-catecholamine neurotransmitter systems with particular promise for unipolar and bipolar depression include excitatory amino acid neurotransmitter modulators (eg, riluzole, N-methyl-D-aspartate antagonists, and AMPA receptor potentiators) and neuropeptide antagonists (targeting corticotropin releasing factor-1 and neurokinin receptors). Potential antidepressant and mood-stabilizing agents targeting common intracellular pathways of known monoaminergic agents and lithium/mood stabilizers are also reviewed, such as neurotrophic factors, extracellular receptor-coupled kinase (ERK) mitogen-activated protein (MAP) kinase and the bcl-2 family of proteins, and inhibitors of phosphodiesterase, glycogen synthase kinase-3, and protein kinase C. A major thrust of drug discovery in mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as intravenous administration of ketamine), as well as identify drugs used routinely in non-psychiatric diseases for their antidepressant and mood-stabilizing properties.

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Section: Glycogen Synthase Kinase-3 (Bipolar Disorder and Major Deprementioning

confidence: 84%

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Mathew

Manji

Charney

2008

Neuropsychopharmacol

206

140

View full text Add to dashboard Cite

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“…GSK3␤ has also recently been identified as a common target for SSRIs, tricyclic antidepressants, and antipsychotics (5,7,9). Furthermore, reduction of GSK3␤ phosphorylation, resulting in kinase activation, in the prefrontal cortex has been associated with major depressive disorders in a cohort of suicide victims (49). Although these observations suggest an involvement of GSK3␤ signaling in the etiology of various disorders and the action of psychoactive drugs, a direct role for GSK3␤ in the regulation of 5-HT related behaviors or the effect of drugs enhancing 5-HT neurotransmission has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

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

337

317

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Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3␤ (GSK3␤), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3␤ signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3␤ and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism S erotonin (5-HT) is involved in multiple aspects of normal brain functions ranging from the regulation of mood to the control of appetite and social interactions (1-3). Several studies have suggested a contribution of abnormal 5-HT transmission in various human psychiatric conditions and drugs acting on 5-HT neurotransmission are commonly used for the management of major depression, anxiety disorder, obsessive-compulsive disorder, autism, and schizophrenia (1-3). Although drugs that influence the 5-HT system can affect histone acetylation, modulate production of brain-derived neurotrophic factor, increase neural progenitor cell proliferation, and inhibit glycogen synthase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the mechanisms underlying the regulation of behavior by 5-HT are still obscure.There are indications that pharmacologic manipulations of 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6-9). For instance, multiple classes of 5-HT drugs, including selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antipsychotics (5, 7, 9), inhibit brain GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, 10-12), which is often used in combination with antidepressants for the management of certain mood disorders (13). However, whether these changes in GSK3␤ are incidental or contribute to the regulation of 5-HT-related abnormal behaviors is unexplored (5...

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“…AKT function has been associated with prefrontal cortex structural alterations in both humans and mice (Lai et al, 2006;Tan et al, 2008), together with alterations in social information processing and mental health conditions associated with disordered mood, such as depression, autism, bipolar disorder and schizophrenia (De Lacy and King, 2013;Ebert and Greenberg, 2013;Emamian, 2012;Kitagishi et al, 2012;Marsden, 2013;Zheng et al, 2012). Resveratrol increased Thr308 phosphorylation of AKT, noteworthy as the brains of depressed (suicide and non-suicide) subjects exhibit prefrontal cortex reductions in AKT enzymatic activity, including Thr308 phosphorylation, and also in the absence of protein level changes (Dwivedi et al, 2010;Kar ege et al, 2011Kar ege et al, , 2007. Furthermore, in trying to understand the mechanisms at play, it is worth noting that, where present, resveratrol administration-induced increases in AKT activation were observed selectively in the nuclear fractions, potentially related to oxidative activity that can trigger such nuclear activation (Uranga et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Poirier

Imamura

Zanoletti

et al. 2014

Journal of Psychiatric Research

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a b s t r a c tAdolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28e42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

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Alteration in Kinase Activity But Not in Protein Levels of Protein Kinase B and Glycogen Synthase Kinase-3β in Ventral Prefrontal Cortex of Depressed Suicide Victims

Cited by 190 publications

References 29 publications

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Novel Drugs and Therapeutic Targets for Severe Mood Disorders

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

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