Genome-Wide Association-, Replication-, and Neuroimaging Study Implicates HOMER1 in the Etiology of Major Depression

Rietschel, Marcella; Mattheisen, Manuel; Frank, Josef; Treutlein, Jens; Degenhardt, Franziska; Breuer, René; Steffens, Michael; Mier, Daniela; Esslinger, Christine; Walter, Henrik; Kirsch, Peter; Erk, Susanne; Schnell, Knut; Herms, Stefan; Wichmann, Heinz‐Erich; Schreiber, Stefan; Jöckel, Karl Heinz; Strohmaier, Jana; Roeske, D.; Haenisch, Britta; Groß, Magdalena; Hoefels, Susanne; Lucae, Susanne; Binder, Elisabeth B.; Wienker, Thomas F.; Schulze, Thomas G.; Schmäl, Christine; Zimmer, Andreas; Juraeva, Dilafruz; Brors, Benedikt; Bettecken, Thomas; Meyer‐Lindenberg, Andreas; Müller‐Myhsok, Bertram; Maier, Wolfgang; Nöthen, Markus M.; Cichon, Sven

doi:10.1016/j.biopsych.2010.05.038

Cited by 161 publications

(146 citation statements)

References 34 publications

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“…The potential involvement of Homer1a in depression-like behavior has been suggested in several reports Szumlinski et al, 2005Szumlinski et al, , 2006Kato, 2009;Rietschel et al, 2010;Sun et al, 2011). Collectively, the data on Homer1 suggest distinct roles for both isoforms: Homer1a and Homer1b/c in behavioral response to stress.…”

Section: Homer1a In Depression and Anti Depressant Treatmentsmentioning

confidence: 69%

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

Serchov

Heumann

Calker

et al. 2016

Biological Chemistry

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Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint mechanism for antidepressant therapy in general. However, the upstream signaling pathways that regulate or induce Homer1a expression are still not well understood. The main focus of the present review is to offer an overview of the current knowledge about the potential role of Homer1a in depression and the signaling pathways responsible for Homer1a regulation. It is suggested here that a detailed characterization of the signaling mechanisms leading to Homer1a expression might provide novel therapeutic targets for antidepressant drug development.

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Section: Homer1a In Depression and Anti Depressant Treatmentsmentioning

confidence: 69%

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

Serchov

Heumann

Calker

et al. 2016

Biological Chemistry

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“…Dysfunction of Homer proteins is implicated in neuropsychiatric disorders and their models (Szumlinski et al, 2006). In particular, Homer1 has been implicated in the etiology of major depression by a recent genome-wide association study (Rietschel et al, 2010). Orsetti et al (2008) reported downregulation of Homer1 mRNA in rats under CMS without pinpointing Homer1a.…”

Section: Pyramidal Cell Hyperexcitability Associated With Depression-mentioning

confidence: 99%

“…In rats subjected to a model ECT [electroconvulsive shock (ECS)], we revealed that cortical pyramidal cell excitability was reduced, depending on Homer1a. Homer1, implicated in the etiology of major depression (Rietschel et al, 2010), is a member of the scaffold protein family Homer and consists of two splice variants (Brakeman et al, 1997;Kato et al, 1997). Homer1b/c, a constitutively expressed variant, binds to receptors, including metabotropic glutamate receptors (mGluRs), and cross-links them by selfdimerization.…”

Section: Introductionmentioning

confidence: 99%

Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study

Sun¹,

Wang²,

Wang³

et al. 2011

J. Neurosci.

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Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

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“…In contrast, the early immediate gene Homer1a is thought to act as dominant negative isoform disrupting mGluR5/Homer1b/c coupling and predominantly modulates ligand-independent mGluR5 signaling (Ango et al, 2001). Clinical studies provided first evidence that Homer1 is involved in the development of major depressive disorders (Rietschel et al, 2010), whereas preclinical studies describe its importance in anxiety-and depression-related behavior (Szumlinski et al, 2005;Lominac et al, 2005), memory formation , fear (Tronson et al, 2010), and reward-related behaviors (Jaubert et al, 2007;Szumlinski et al, 2004). Furthermore, the activityinduced splice variant Homer1a (Brakeman et al, 1997) has been shown to be crucially involved in behavioral alterations that are related to depression (Celikel et al, 2007;Mahan et al, 2012) and anxiety .…”

Section: Introductionmentioning

confidence: 99%

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Wagner

Hartmann

Labermaier

et al. 2014

Neuropsychopharmacol

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Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.

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Genome-Wide Association-, Replication-, and Neuroimaging Study Implicates HOMER1 in the Etiology of Major Depression

Cited by 161 publications

References 34 publications

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy

Increase in Cortical Pyramidal Cell Excitability Accompanies Depression-Like Behavior in Mice: A Transcranial Magnetic Stimulation Study

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

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