Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves μ-Opioid Receptors

Xu, Changqing; Fitting, Sylvia

doi:10.3389/fnins.2016.00497

Cited by 14 publications

(9 citation statements)

References 112 publications

(138 reference statements)

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“…The balance of excitatory and inhibitory tone within frontal cortico-BG-thalamocortical loops is essential for modulating behavioral control ( Christakou et al, 2001 ; Muir et al, 1996 ; Naaijen et al, 2015 ), and HAND is associated with the dysregulation of both glutamatergic and GABAergic systems ( Buzhdygan et al, 2016 ; Gelman et al, 2012 ; Musante et al, 2010 ; Potter et al, 2013 ; Xu and Fitting, 2016 ; Xu et al, 2016 ). Accordingly, Tat-induced dysregulation of the ACC, striatum, and thalamus may result in decreased control of novelty-exploration, adaptability, and pre-attentive filtering.…”

Section: Discussionmentioning

confidence: 99%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

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HIV-1 selectively disrupts neuronal integrity within specific brain regions, reflecting differences in viral tropism and/or the regional differences in the vulnerability of distinct neuronal subpopulations within the CNS. Deficits in prefrontal cortex (PFC)-mediated executive function and the resultant loss of behavioral control are a particularly debilitating consequence of neuroHIV. To explore how HIV-1 disrupts executive function, we investigated the effects of 48 h, 2 and/or 8 weeks of HIV-1 Tat exposure on behavioral control, synaptic connectivity, and neuroimmune function in the anterior cingulate cortex (ACC) and associated cortico-basal ganglia (BG)-thalamocortical circuitry in adult, Tat transgenic male mice. HIV-1 Tat exposure increased novelty-exploration in response to novel food, flavor, and environmental stimuli, suggesting that Tat triggers increased novelty-exploration in situations of competing motivation (e.g., drive to feed or explore vs. fear of novel, brightly lit open areas). Furthermore, Tat induced adaptability in response to an environmental stressor and pre-attentive filtering deficits. The behavioral insufficiencies coincided with decreases in the inhibitory pre- and post-synaptic proteins, synaptotagmin 2 and gephyrin, respectively, in the ACC, and alterations in specific pro- and anti-inflammatory cytokines out of 23 assayed. The interaction of Tat exposure and the resultant time-dependent, selective alterations in CCL4, CXCL1, IL-12p40, and IL-17A levels in the PFC predicted significant decreases in adaptability. Tat decreased dendritic spine density and cortical VGLUT1 inputs, while increasing IL-1β, IL-6, CCL5, and CCL11 in the striatum. Alternatively, IL-1α, CCL5, and IL-13 were decreased in the mediodorsal thalamus despite the absence of synaptic changes. Thus, HIV-1 Tat appears to uniquely and systematically disrupt immune regulation and the inhibitory and excitatory synaptic balance throughout the ACC-BG-thalamocortical circuitry resulting in a loss of behavioral control.

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Section: Discussionmentioning

confidence: 99%

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Nass

Hahn

McLane

et al. 2020

Brain, Behavior, & Immunity - Health

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show abstract

“…Furthermore, FHC upregulation or dampening of µOR expressing parvalbumin, somatostatin, or cholecystokinin interneurons may disrupt their ability to tune the excitation of nearby excitatory or inhibitory neurons (Artinian and Lacaille, 2018; Ferguson and Gao, 2018; Whissell et al, 2019). Therefore, altered GABAergic transmission, which is an important component of HAND pathology (Buzhdygan et al, 2016; Marks et al, 2016; Xu and Fitting, 2016), may be further disrupted by opioids.…”

Section: Discussionmentioning

confidence: 99%

“…Many patients with HIV are infected by sharing opioid injection equipment with other infected individuals. Additionally, clinical and preclinical studies suggest that µ-opioid use worsens HAND symptoms (Bandaru et al, 2011; Byrd et al, 2011; Guo et al, 2012; Fitting et al, 2014; Pitcher et al, 2014; El-Hage et al, 2015; Xu and Fitting, 2016). This may be due, at least in part, to µ-opioid receptor (µOR)-mediated inhibition of the CXCL12/CXCR4 chemokine signaling axis in cortical neurons (Sengupta et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons

Nash

Tarn

Irollo

et al. 2019

eNeuro

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HIV-associated neurocognitive disorders (HAND) remain prevalent and are aggravated by µ-opioid use. We have previously shown that morphine and other µ-opioids may contribute to HAND by inhibiting the homeostatic and neuroprotective chemokine receptor CXCR4 in cortical neurons, and this novel mechanism depends on upregulation of the protein ferritin heavy chain (FHC). Here, we examined the cellular events and potential mechanisms involved in morphine-mediated FHC upregulation using rat cortical neurons of either sex in vitro and in vivo. Morphine dose dependently increased FHC protein levels in primary neurons through µ-opioid receptor (µOR) and Gαi-protein signaling. Cytoplasmic FHC levels were significantly elevated, but nuclear FHC levels and FHC gene expression were unchanged. Morphine-treated rats also displayed increased FHC levels in layer 2/3 neurons of the prefrontal cortex. Importantly, both in vitro and in vivo FHC upregulation was accompanied by loss of mature dendritic spines, which was also dependent on µOR and Gαi-protein signaling. Moreover, morphine upregulated ferritin light chain (FLC), a component of the ferritin iron storage complex, suggesting that morphine altered neuronal iron metabolism. Indeed, prior to FHC upregulation, morphine increased cytoplasmic labile iron levels as a function of decreased endolysosomal iron. In line with this, chelation of endolysosomal iron (but not extracellular iron) blocked morphine-induced FHC upregulation and dendritic spine reduction, whereas iron overloading mimicked the effect of morphine on FHC and dendritic spines. Overall, these data demonstrate that iron mediates morphine-induced FHC upregulation and consequent dendritic spine deficits and implicate endolysosomal iron efflux to the cytoplasm in these effects.

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“…Additionally, altered neuronal activity in HAND models can be exacerbated by comorbid drug abuse. For example, cocaine increased the excitability of pyramidal cells in the layer V and VI prefrontal cortex of male HIV-transgenic rats [ 109 ], opioids reduced GABAergic neurotransmission in the striatum of male and female mice in the presence of tat [ 110 , 111 ], and methamphetamine affects synaptic and neuroplasticity markers in male and female HIV models [ 112 , 113 ]. These findings are in line with the complex and multifactorial HAND scenario observed in the clinic and highlight our incomplete knowledge of the disorder.…”

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

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Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves μ-Opioid Receptors

Cited by 14 publications

References 112 publications

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

Morphine-Induced Modulation of Endolysosomal Iron Mediates Upregulation of Ferritin Heavy Chain in Cortical Neurons

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

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