Metabotropic Glutamate Receptor 5/Homer Interactions Underlie Stress Effects on Fear

Tronson, Natalie C.; Guzmán, Yomayra F.; Guedea, Anita L.; Huh, Kyu Hwan; Gao, Can; Schwarz, Martin K.; Radulovic, Jelena

doi:10.1016/j.biopsych.2010.09.004

Cited by 66 publications

(56 citation statements)

References 44 publications

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“…We also observed a significant decrease in Homer1/mGluR5 coupling following chronic social defeat. This effect cannot be specified to either Homer1 splice variant at the moment because of the lack of specific and reliable antibodies targeting Homer1a (Tronson et al, 2010). Further studies will be required to unravel the functional consequence of this effect.…”

Section: Discussionmentioning

confidence: 99%

“…However, the late onset of therapeutic effects as well as unsatisfactory relapse rates and side effects illustrates the need for improved therapeutics (Thase, 2006). Recent studies have provided convincing evidence that dysregulation of glutamate signaling, mainly via its postsynaptic receptors a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and metabotropic glutamate receptors (mGluRs), contributes to the emergence of psychiatric disorders (Kendell et al, 2005;Sanacora et al, 2012;Mathews et al, 2012;Yim et al, 2012;Tronson et al, 2010). Modulation of glutamate receptor function has therefore been proposed as a promising target for antidepressant, anxiolytic, and antipsychotic drug development .…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Wagner

Hartmann

Labermaier

et al. 2014

Neuropsychopharmacol

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“…Evidence exists for effects of both a single restraint event and repeated restraints on subsequent fear learning. Several studies have shown increased freezing upon exposure to a context previously paired with shock in rodents that have undergone brief (30 min-2 h) restraint (Cordero et al 2003;Rodriguez Manzanares et al 2005;Tronson et al 2010), whereas other studies utilizing repeated restraint have observed increased freezing upon exposure to a tone previously paired with shock (Meyer et al 2014;Suvrathan et al 2014;Baratta et al 2015). The degree to which restraint stress affects fear learning, generalization, extinction rate, or extinction retention differs, depending on the method and duration of restraint, the varying delays between the stress and fear conditioning and differences in the amount of shock utilized during conditioning (Miracle et al 2006;Andero et al 2011Andero et al , 2013Chauveau et al 2012).…”

Section: Stress-enhanced Fear Learning Modelsmentioning

confidence: 99%

“…Several recent reviews have covered the broad array of neurobiological players that have been found to mediate SEFL, such as glucocorticoids, glutamate, glycine, and cytokines (Cordero et al 2003;Akirav and Maroun 2007;Iwamoto et al 2007;Kohda et al 2007;Yamamoto et al 2009;Tronson et al 2010;Jones et al 2015;Maren and Holmes 2016;Perusini et al 2016). However, in spite of the contribution of epigenetic mechanisms to stress and numerous aspects of fear memory independently, very little work has been done in the realm of epigenetics at the crossroads between stress and fear memory.…”

Section: The Neuroepigenetics Of Stress-enhanced Fear Learningmentioning

confidence: 99%

The potential of epigenetics in stress-enhanced fear learning models of PTSD

et al. 2016

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Prolonged distress and dysregulated memory processes are the core features of post-traumatic stress disorder (PTSD) and represent the debilitating, persistent nature of the illness. However, the neurobiological mechanisms underlying the expression of these symptoms are challenging to study in human patients. Stress-enhanced fear learning (SEFL) paradigms, which encompass both stress and memory components in rodents, are emerging as valuable preclinical models of PTSD. Rodent models designed to study the long-term mechanisms of either stress or fear memory alone have identified a critical role for numerous epigenetic modifications to DNA and histone proteins. However, the epigenetic modifications underlying SEFL remain largely unknown. This review will provide a brief overview of the epigenetic modifications implicated in stress and fear memory independently, followed by a description of existing SEFL models and the few epigenetic mechanisms found to date to underlie SEFL. The results of the animal studies discussed here highlight neuroepigenetics as an essential area for future research in the context of PTSD through SEFL studies, because of its potential to identify novel candidates for neurotherapeutics targeting stress-induced pathogenic memories.Post-traumatic stress disorder (PTSD) is triggered by experiencing or witnessing a traumatic event and is characterized by pathogenic memory (e.g., recurrent, involuntary memories that trigger intense stress), avoidance of reminders, hyperarousal and reactivity, negative mood, cognitive alterations, and a persistence of symptoms for at least 1 mo. Although only a fraction of people exposed to trauma develop PTSD, a history of stress exposure prior to witnessing a traumatic event increases the risk (Breslau et al. 2014). Therefore, some animal models of PTSD use multidimensional stress and fear memory paradigms to model the disorder. In stress-enhanced fear learning (SEFL), a rodent is exposed to a stressor or combination of stressors prior to undergoing classical fear conditioning. Models that utilize SEFL closely reproduce many core symptoms of PTSD, including enhanced fear learning, generalized anxiety, heightened startle, and impaired extinction.

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The role of Homer1c in metabotropic glutamate receptor-dependent long-term potentiation

et al. 2013

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Group I metabotropic glutamate receptors (mGluR1/5) play a role in synaptic plasticity and they demonstrate direct interactions with the neuronal Homer1c protein. We have previously shown that Homer1c can restore the plasticity deficits in Homer1 knockout mice (H1-KO). Here, we investigated the role of Homer1c in mGluR-dependent synaptic plasticity in wild-type mice, H1-KO, and H1-KO mice overexpressing Homer1c (KO+H1c). We used a form of plasticity induced by activation of mGluR1/5 that transforms short-term potentiaion (STP) induced by a subthreshold theta burst stimulation into long-term potentiation (LTP). We have shown that although acute hippocampal slices from wild-type animals can induce LTP using this stimulation protocol, H1-KO only show STP. Gene delivery of Homer1c into the hippocampus of H1-KO mice rescued LTP to wild-type levels. This form of synaptic plasticity was dependent on mGluR5 but not mGluR1 activation both in wild-type mice and in KO+H1c. mGluR1/5-dependent LTP was blocked with inhibitors of the MEK-ERK and PI3K-mTOR pathways in KO+H1c mice. Moreover, blocking Homer1c–mGluR5 interactions prevented the maintenance of LTP in acute hippocampal slices from KO+H1c. These data indicate that Homer1c–mGluR5 interactions are necessary for mGluR-dependent LTP, and that mGluR1/5-dependent LTP involves PI3K and ERK activation.

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Metabotropic Glutamate Receptor 5/Homer Interactions Underlie Stress Effects on Fear

Cited by 66 publications

References 44 publications

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

The potential of epigenetics in stress-enhanced fear learning models of PTSD

The role of Homer1c in metabotropic glutamate receptor-dependent long-term potentiation

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