Epigenetic Modulation of Homer1a Transcription Regulation in Amygdala and Hippocampus with Pavlovian Fear Conditioning

Mahan, Amy; Mou, Liping; Shah, Nirali; Hu, Jia; Worley, Paul F.; Ressler, Kerry J.

doi:10.1523/jneurosci.3308-11.2012

Cited by 102 publications

(92 citation statements)

References 52 publications

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“…Previous studies manipulating histone acetylation have not consistently found effects on auditory fear, even with systemic infusions of broad-spectrum HAT or HDAC inhibitors. Some of these studies find effects on context, but not auditory fear (Korzus et al, 2004;Mahan et al, 2012;Wood et al, 2005), whereas others find effects on both context and auditory fear (Alarcon et al, 2004;Bredy and Barad, 2008;Chwang et al, 2007;Gao et al, 2010;Guan et al, 2009;Maddox et al, 2013b). Similarly, the effects of systemic HDAC3 inhibition are mixed.…”

Section: Discussionmentioning

confidence: 99%

“…Histone acetylation is a fundamental chromatin regulatory mechanism that is dynamically controlled during learning (Levenson et al, 2004;Maddox et al, 2013b;Mahan et al, 2012;Miller et al, 2008) and critically involved in long-term memory formation (Barrett et al, 2011;Bieszczad et al, 2015;Bredy and Barad, 2008;Guan et al, 2009;Maddox et al, 2013b;McQuown et al, 2011a;Vecsey et al, 2007;Wood et al, 2005). Histone acetylation is modulated through two competing classes of enzymes: HATs and HDACs.…”

Section: Introductionmentioning

confidence: 99%

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Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

Kwapis

Alaghband

López

et al. 2016

Neuropsychopharmacol

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Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

Kwapis

Alaghband

López

et al. 2016

Neuropsychopharmacol

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“…(Gupta-Agarwal et al 2012). Similarly, cued fear conditioning as well as BDNF-induced plasticity in cell culture resulted in different patterns of histone PTMs at the homer1 promoter in hippocampal and amygdala neurons (Mahan et al 2012), indicating that the same gene can be differentially regulated by identical stimuli in different regions of the brain. Epigenetic modifications can be further localized to discrete subregions of the hippocampus.…”

Section: Epigenetic Mechanisms Regulate Memory Across Tasks and Brainmentioning

confidence: 99%

“…Importantly, stimulation of ERK signaling (Levenson et al 2004) and treatment with HDAC inhibitors ) produced gene-and histone-specific changes in PTMs, indicating that distinct signaling cascades may establish precise histone codes that correspond to particular types of memory ). Moreover, BDNF activity regulates the consolidation of contextual fear conditioning through alterations of histone-and residue-specific post-translational modifications at the homer1 promoter in the hippocampus and the amygdala (Mahan et al 2012). In addition, nitric oxide (NO) has been implicated in histone acetylation by regulating the dissociation of HDAC2 from CREB-regulated gene promoters (Nott et al 2008;Nott and Riccio 2009) …”

Section: Epigenetic Modifications Are Regulated In Response To Specifmentioning

confidence: 99%

Epigenetic regulation of memory formation and maintenance

2013

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Understanding the cellular and molecular mechanisms underlying the formation and maintenance of memories is a central goal of the neuroscience community. It is well regarded that an organism's ability to lastingly adapt its behavior in response to a transient environmental stimulus relies on the central nervous system's capability for structural and functional plasticity. This plasticity is dependent on a well-regulated program of neurotransmitter release, post-synaptic receptor activation, intracellular signaling cascades, gene transcription, and subsequent protein synthesis. In the last decade, epigenetic markers like DNA methylation and post-translational modifications of histone tails have emerged as important regulators of the memory process. Their ability to regulate gene transcription dynamically in response to neuronal activation supports the consolidation of long-term memory. Furthermore, the persistent and self-propagating nature of these mechanisms, particularly DNA methylation, suggests a molecular mechanism for memory maintenance. In this review, we will examine the evidence that supports a role of epigenetic mechanisms in learning and memory. In doing so, we hope to emphasize (1) the widespread involvement of these mechanisms across different behavioral paradigms and distinct brain regions, (2) the temporal and genetic specificity of these mechanisms in response to upstream signaling cascades, and (3) the functional outcome these mechanisms may have on structural and functional plasticity. Finally, we consider the future directions of neuroepigenetic research as it relates to neuronal storage of information.

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“…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 . Moreover, prenatal stress was shown to alter Homer1a and Homer1b/c expression in several corticolimbic structures, including the hippocampus (Ary et al, 2007).…”

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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Epigenetic Modulation of Homer1a Transcription Regulation in Amygdala and Hippocampus with Pavlovian Fear Conditioning

Cited by 102 publications

References 52 publications

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

Epigenetic regulation of memory formation and maintenance

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

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