Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

Authement, Michael E.; Kodangattil, Jayaraj N.; Gouty, Shawn; Rusnak, Milan; Symes, Aviva J.; Cox, Brian M.; Nugent, Fereshteh S.

doi:10.1016/j.neuron.2015.05.024

Cited by 52 publications

(75 citation statements)

References 57 publications

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“…In fact, MD modifies DA signaling from the VTA through epigenetic modifications of critical signaling pathways involved in trafficking of GABA A receptors onto VTA DA neurons (25). Considering the potent inhibitory control of VTA DA neurons by the LHb, we chose to use the same model of severe early life stress in this work to determine whether the response of LHb neurons to extrahypothalamic CRF is affected by exposure to early life stress.…”

Section: Resultsmentioning

confidence: 99%

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

et al. 2018

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Centrally released corticotropin releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, increased activity of the LHb is associated with addiction, depression, schizophrenia and behavior disorders. Here, we found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small- and large-conductance SK- and BK-type K+ channels. CRF also reduced inhibitory GABAergic synaptic transmission onto LHb neurons through endocannabinoid (eCB)-mediated retrograde signaling. Maternal deprivation is a severe early life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any significant changes in Crh or Crhr1 expression. Notably, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders.

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Section: Resultsmentioning

confidence: 99%

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

et al. 2018

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“…Rodent studies have often employed a prolonged single episode (24 h) of maternal deprivation or periodic brief episodes (3–6 h) of maternal separation within the first 2 postnatal weeks to examine effects of early‐life stress. Both paradigms are sufficient to alter the number of DA neuronal and glial cells, affect the rate of cell proliferation and apoptosis, and promote aberrant DA signaling in the VTA and SN in rodents . Such dysregulation at least partly involves epigenetic modifications altering neuronal and synaptic plasticity, which likely mediate long‐term changes in the expression and function of DA neurons, receptors, and transporters observed in the key DA‐innervated brain regions, including the striatum (STR) and PFC .…”

Section: Dopamine Systemmentioning

confidence: 99%

Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways

Kim

Kwok

Mayes

et al. 2016

Annals of the New York Academy of Sciences

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Substance addiction may follow a chronic, relapsing course and critically undermine the physical and psychological well-being of the affected individual and the social units of which the individual is a member. Despite the public health burden associated with substance addiction, treatment options remain suboptimal, with relapses often seen. The present review synthesizes growing insights from animal and human research to shed light upon developmental and neurobiological pathways that may increase susceptibility to addiction. We examine the dopamine system, the oxytocin system, and the glucocorticoid system, as they are particularly relevant to substance addiction. Our aim is to delineate how early adverse experience may induce long-lasting alterations in each of these systems at molecular, neuroendocrine, and behavioral levels and ultimately lead to heightened vulnerability to substance addiction. We further discuss how substance addiction in adulthood may increase the risk of suboptimal caregiving for the next generation, perpetuating the intergenerational cycle of early adverse experiences and addiction.

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“…In our ELS studies, we use a model of child neglect, maternal deprivation (MD), where pups are isolated from the dam for a 24‐hr period. MD preferentially targeted GABAergic synapses onto VTA DA neurons and impaired the ability of these synapses to exhibit Hebbian spike timing–dependent plasticity (STDP) through the disruption of A‐kinase anchoring protein (AKAP150) (Authement et al, 2015). AKAP150 scaffold protein (AKAP150 in rodents, the human ortholog being AKAP79/AKAP5) plays a pivotal role in synaptic plasticity through anchoring of protein kinase A (PKA), calcineurin, and other signaling molecules such as PKC to their substrates, such as synaptic receptors including AMPA, NMDA, and GABA A receptors, and ion channels (Sanderson & Dell'acqua, 2011; Wild & Dell'Acqua, 2017).…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

Shepard

Langlois

Authement

et al. 2020

J of Neuroscience Research

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Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long-term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A-kinase anchoring protein (AKAP150).Importantly, these MD-induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell-attached and whole-cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non-MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD-induced VTA DA hyperexcitability. This MD-induced DA neuronal hyperexcitability could also be normalized at 24 hr after injection of the class 1 HDAC inhibitor, CI-994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC-mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology. K E Y W O R D SAKAP, dopamine, epigenetics, HDAC, histone acetylation, VTA The authors declare no competing financial interests.

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Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

Cited by 52 publications

References 57 publications

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

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