Aging and HIV-1 alter the function of specific K+ channels in prefrontal cortex pyramidal neurons

Chen, Lihua; Khodr, Christina E.; Al‐Harthi, Lena; Hu, Xiu‐Ti

doi:10.1016/j.neulet.2019.134341

Cited by 15 publications

(16 citation statements)

References 26 publications

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“…in is toxic, which could induce hyperactivity (abnormally-increased firing that can drive neurons to the status of overactivation [ 29 ]); injury (that reduces the synapses, dendritic processes, synaptic activity [ 30 ], and connectivity among neurons and glial cells [ 31 , 32 ]); aberrant and loss of firing (due to overactivation-induced inactivation) [ 29 ] which could eventually lead to death of pyramidal neurons in the HIPP and PFC [ 6 , 23 ], and decline of cognitive function, dictated by neuronal circuits. It is also worth noting that aging, per se , is associated with a significant decrease in the mPFC neuronal activity, which could initiate at middle age [ 33 ], even without the impact of AD or HIV/AIDS ( Figure 1 ). Taken together, these findings strongly suggest that AD-and/or HAND-induced decrease of neuronal activity (i.e., overactivation-induced inactivation) could be worsened during aging, and such comorbid conditions will almost inevitably exacerbate the cognitive dysfunction in AD and HAND patients.…”

Section: Background For a New Hypothesismentioning

confidence: 99%

“…It is worth noting that hyperactivity of the PFC (with abnormally-increased [Ca 2+ ] in ) appears to be prevalent in both AD [ 1 , 16 , 22 ] and HIV/AIDS [ 46 , 47 ] which could induce neurotoxicity and drive overactivated pyramidal neurons to firing loss [ 13 , 29 ], similar to a consequence of aging [ 48 ]. Our published studies also demonstrate that, in the context of neuroHIV, hyperactivity of mPFC pyramidal neuron [ 13 - 15 , 29 , 33 , 48 ] disturbs their glutamate output to the striatum, which abnormally increases firing of GABAergic striatal neurons [ 26 ]. Thus, it is likely that similar neuronal dysregulation may also occur in AD patients.…”

Section: Background For a New Hypothesismentioning

confidence: 99%

“…Thus, it is likely that similar neuronal dysregulation may also occur in AD patients. Given that (1) Decreased activity and injury/loss of HIPP and PFC neurons are associated with ADRD and HIV-associated dementia, (2) Aging likely exacerbates such conditions by inducing additional loss of neuron firing [ 33 ], and (3) ARVs-induced hyperactivity is mediated by overactivation of L-channels in mPFC pyramidal neurons following chronic treatment [ 49 ], it is the time to pay equal attention for the dysfunction of mPFC and striatum in AD and HAND, in addition to the HIPP.…”

Section: Background For a New Hypothesismentioning

confidence: 99%

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A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV

Xiu-Ti¹

2020

Alzheimers Dis Dement

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Both Alzheimer’s disease (AD) and HIV-associated neurocognitive disorders (HAND) could progress to dementia, a severe consequence of neurodegenerative diseases. Cumulating evidence suggests that the β-amyloid (Aβ) theory, currently thought to be the predominant mechanism underlying AD and AD-related dementia (ADRD), needs re-evaluation, considering all treatments and new drug trials based upon this theory have been unsuccessful. Similar intention for treating HAND, including HIV-associated dementia (HAD), has also failed. Thus, novel theory, hypothesis, and therapeutic strategies are desperately needed for future study and effective treatments of AD/ADRD and HAND. There are numerous potential upstream mechanisms that may cause AD and/or HAND; but it is unrealistic to identify all of them. However, it is realistic and feasible to intervene the downstream mechanism of these two devastating neurodegenerative diseases by blocking the final common path to neurotoxicity mediated by overactivation of NMDA receptors (NMDARs) and voltage-gated calcium channels (VGCCs). Such a combined pharmacological intervention will likely ameliorate neuronal Ca 2+ homeostasis by diminishing overactivated NMDAR and VGCC-mediated Ca 2+ dysregulation (i.e., by reducing excessive Ca 2+ influx and intracellular levels, [Ca 2+ ]in)-induced hyperactivity, injury, and death of neurons in the critical brain regions that regulate neurocognition in the context of AD/ADRD or HAND, especially during aging. Here we present a novel theoretical concept, hypothesis, and working model for switching the battlefield from searching-and-fighting the original mechanism that may cause AD or HAND, to abolishing AD- and neuroHIV-induced neurotoxicity mediated by NMDAR and VGCC over activation, which may ultimately improve the therapeutic strategies for treating AD and HAND.

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Section: Background For a New Hypothesismentioning

confidence: 99%

Section: Background For a New Hypothesismentioning

confidence: 99%

Section: Background For a New Hypothesismentioning

confidence: 99%

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A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV

Xiu-Ti¹

2020

Alzheimers Dis Dement

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“…There is growing evidence that the prevalence of comorbidities and other age-related conditions including geriatric syndromes, functional or neurocognitive problems, polypharmacy or social difficulties are higher in PWH than in their uninfected counterparts (Guaraldi et al, 2019 ; Winston and Spudich, 2020 ). Limited information is available regarding the optimal clinical management of older PWH (Chen et al, 2019 ; Guaraldi et al, 2019 ; Guo and Buch, 2019 ). Chronic neuroinflammation has been associated with altered synaptic connectivity and BBB function, and with neuronal injury (Bandera et al, 2019 ; Guaraldi et al, 2019 ).…”

Section: Altered Waste Clearance and Abnormal Aging In Handmentioning

confidence: 99%

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

Tice¹,

McDevitt

Langford³

2020

Front. Cell. Infect. Microbiol.

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The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.

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“…Chronic treatment with tenovovir, 3TC, and efavirenz also disturbs activity of hippocampal pyramidal neurons and memory impairments in rats ( Akang, 2019 ), while acute ARV treatment reduces bioenergetic function in nerve terminals isolated from the striatum ( Stauch et al, 2017 ). It is worth noting that 1) the prefrontal cortex, hippocampus, and striatum are the key regulators of cognition; but they are also most susceptible and vulnerable to HIV ( Ferris et al, 2008 ; Manji et al, 2013 ; Hu, 2016 ); and (ii) neurotoxicity induced by ARVs appears to be associated with dysregulation of neuronal Ca 2+ homeostasis (i.e., excessive intracellular free calcium, [Ca 2+ ] in ) ( Robertson et al, 2012 ; Romo et al, 2012 ; Akay et al, 2014 ; Apostolova et al, 2015 ; Underwood et al, 2015 ; Vivithanaporn et al, 2016 ), similar to that induced by HIV ( Wayman et al, 2012 , 2015 , 2016 ; Napier et al, 2014 ; Khodr et al, 2016 , 2018 ; Chen et al, 2019 ). Collectively, these studies suggest that the site effects of cART disturb neuronal activity in the brain regions that regulate neurocognition, and therefore indicate the necessity to elucidate the mechanism by which ARVs disrupt the brain function.…”

Section: Introductionmentioning

confidence: 99%

Triumeq Increases Excitability of Pyramidal Neurons in the Medial Prefrontal Cortex by Facilitating Voltage-Gated Ca2+ Channel Function

Chen

Al‐Harthi

2021

Front. Pharmacol.

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Combination antiretroviral therapy (cART) suppresses HIV-1 replication, improves immune function, and prolongs the life of people living with HIV (PLWH). However, cART also induces neurotoxicity that could complicate HIV-induced neurodegeneration while reduce its therapeutic efficacy in treating HIV/AIDS. Triumeq is a first-line cART regimen, which is co-formulated by three antiretroviral drugs (ARVs), lamivudine (3TC), abcavir (ABC), and dolutegravir (DTG). Little is known about potential side effects of ARVs on the brain (including those co-formulating Triumeq), and their mechanisms impacting neuronal activity. We assessed acute (in vitro) and chronic (in vivo) effects of Triumeq and co-formulating ARVs on pyramidal neurons in rat brain slices containing the medial prefrontal cortex (mPFC) using patch-clamp recording approaches. We found that acute Triumeq or 3TC in vitro significantly increased firing of mPFC neurons in a concentration- and time-dependent manner. This neuronal hyperactivity was associated with enhanced Ca2+ influx through voltage-gated Ca2+ channels (VGCCs). Additionally, chronic treatment with Triumeq in vivo for 4 weeks (4 wks) also significantly increased firing and Ca2+ influx via VGCCs in mPFC neurons, which was not shown after 2 wks treatment. Such mPFC neuronal hyperexcitability was not found after 4 weeks treatments of individual ARVs. Further, chronic Triumeq exposure in vivo significantly enhanced mRNA expression of low voltage-activated (LVA) L-type Ca2+ channels (Cav1.3 L-channels), while changes in high voltage-activated (HVA) Cav1.2 L-channels were not observed. Collectively, these novel findings demonstrate that chronic cART induces hyperexcitability of mPFC pyramidal neurons by abnormally promoting VGCC overactivation/overexpression of VGCCs (including, but may not limited to, LVA-Cav1.3 L-channels), which could complicate HIV-induced neurotoxicity, and ultimately may contribute to HIV-associated neurocognitive disorders (HAND) in PLWH. Determining additional target(s) of cART in mPFC pyramidal neurons may help to improve the therapeutic strategies by minimizing the side effects of cART for treating HIV/AIDS.

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Aging and HIV-1 alter the function of specific K+ channels in prefrontal cortex pyramidal neurons

Cited by 15 publications

References 26 publications

A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV

A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

Triumeq Increases Excitability of Pyramidal Neurons in the Medial Prefrontal Cortex by Facilitating Voltage-Gated Ca2+ Channel Function

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