Aging alters voltage-gated calcium channels in prefrontal cortex pyramidal neurons in the HIV brain

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

doi:10.1007/s13365-017-0588-y

Cited by 8 publications

(11 citation statements)

References 21 publications

(44 reference statements)

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“…Unexpectedly, the PFC and striatum seem to receive much less attention and, therefore, are understudied compared to the HIPP. 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 ].…”

Section: Background For a New Hypothesismentioning

confidence: 99%

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%

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

Xiu-Ti¹

2020

Alzheimers Dis Dement

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“…Brain slices of rats were prepared, and then evoked action potential (firing) and VGCC activity were assessed among pyramidal neurons from the layer V-VI of the mPFC as described in our previous studies ( Nasif et al, 2005a ; Wayman et al, 2005b ; Napier et al, 2014 ; Wayman et al, 2015 ; Wayman et al, 2016 , Chen et al, 2019 ; Khodr et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…The medial prefrontal cortex (mPFC) plays a critical role in regulating neurocognition; but it is profoundly altered by HIV-1 ( Ferris et al, 2008 ; Hu, 2016 ). HIV-1 induces hyperactivity of glutamatergic pyramidal neurons in the mPFC by causing overactivation of voltage-gated Ca 2+ channels (VGCCs) ( Khodr et al, 2016 ; 2018 ; Napier et al, 2014 ; Wayman et al, 2015 ; 2016 ; 2012 ), in addition to glutamate and NMDA receptor (NMDAR) dysfunction ( Gonzalez-Scarano and Martin-Garcia, 2005 ; King et al, 2006 ). Such Ca 2+ dysregulation-mediated neurotoxicity resulting from NMDAR/VGCC dysfunction may contribute to the underlying mechanism of HAND ( Hu, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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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“…HIV-1 disturbs the functional expression and activity of voltage-gated calcium channel (VGCCs) (changes in evoked Ca 2+ spikes and L-channel expression) in the mPFC in an agedependent way and implies that ion-channel dysfunction associated with HIV-induced medial PreFrontal Cortex (mPFC) hyper-excitability progresses with age/HIV duration [134].…”

Section: Hiv-1 Disrupts the Calcium Signaling In The Brainmentioning

confidence: 99%

Brain Aging in HIV-1 Infection

Santerre¹,

Sawaya²

2018

Advances in HIV and AIDS Control

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It has been shown that patients carrying HIV-1 accumulate damage to cells and tissues that are not directly infected by the virus itself (e.g., neurons). Importantly, these include changes known as HIV-Associated Neurodegenerative Disorder (HAND) leading to the loss of neuronal functions. HAND is an outstanding problem in the clinical management of HIV-1 patients because suppression of infectious virus by cART does not completely block neurodegenerative changes. Neuropsychological studies disclose cognitive alteration (such as loss of Spatial and Declarative Memory) in a substantial proportion of HIV-1 infected patients, and analysis of post-mortem brain tissues isolated from HIV-1 patients treated with cART show signs of neurodegeneration. In the absence of HIV-1 infection of neurons, several mechanisms have been proposed for HAND, including indirect inflammatory effects in the CNS and direct effects of viral proteins (e.g., gp120) shed from activated HIV-1-infected cells. The fact that these viral proteins enter the neurons through several pathways suggests the presence of many competing mechanisms that can contribute to HAND, each of which has its advocates. Their relative contributions to clinical disease in vivo remain to be sorted out, and this is an outstanding problem in HIV research. This chapter will shed some light on the mechanisms used by HIV-1 leading to memory impairments and premature brain aging.

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Aging alters voltage-gated calcium channels in prefrontal cortex pyramidal neurons in the HIV brain

Cited by 8 publications

References 21 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

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

Brain Aging in HIV-1 Infection

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