HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

Clark, John Patrick; Sampair, Christopher; Kofuji, Paulo; Nath, Avindra; Ding, Jian

doi:10.1152/ajpregu.00179.2005

Cited by 29 publications

(36 citation statements)

References 47 publications

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“…Tat30-86 at lower concentrations (10 nM), while not causing a noticeable change in the membrane potential, increased the excitability of the neurons, as demonstrated by the increased number of discharges in response to a step depolarizing current pulse. Haughey et al, 2001;Song et al, 2003;Self et al, 2004,) or potentiation of NMDA receptors secondary to a release of glutamate (Clark et al, 2005). NMDA receptors are characterized by voltage-dependent Mg 2+ block and the reversal potential is close to 0 mV (Mayer et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Tat47-57 and the recombinant Tat1-86 inhibited long-term potentiation in hippocampal slices (Behnisch et al, 2004; Li et al, 2004). Tat1-72 enhanced glutamate transmission in suprachiasmatic nucleus (Clark et al, 2005), while not affecting the release of glutamate and other neurotransmitters from human and rat cortical nerve endings (Feligioni et al, 2003). Several Tat fragments evoked release of acetylcholine from human and rat cerebrocortical synaptosomes (Feligioni et al, 2003).…”

Section: Abstract Calcium Imaging; Electrophysiology; Postsynaptic Cumentioning

confidence: 98%

“…In our study, mEPSCs were abolished by CNQX and AP-5, indicating they are produced by glutamate acting on non-NMDA and NMDA receptors. It has been reported that Tat1-72 enhanced glutamate transmission in neurons of the mouse suprachiasmatic nucleus (Clark et al, 2005). On the other hand, Tat failed to affect the release of glutamate from human and rat cortical nerve endings (Feligioni et al, 2003).…”

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confidence: 96%

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Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons

et al. 2008

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HIV-1 Tat protein is one of the neurotoxins involved in the pathogenesis of HIV-1-associated neuronal disorders. Combined electrophysiological and optical imaging experiments were undertaken to investigate whether HIV-1 Tat30-86, herein referred to as Tat30-86, acted directly or indirectly via the release of glutamate or both and to test its effect on the properties of spontaneous quantal events in cultured cortical neurons. Whole-cell patch recordings were made from cultured rat cortical neurons in either current-or voltage-clamp mode. Tat30-86 (50-1000 nM) induced in a population of cortical neurons a long-lasting depolarization, which was accompanied by a decrease of membrane resistance and persisted in a Krebs solution containing tetrodotoxin (TTX, 0.5 μM). Depolarizations were slightly reduced by pretreatment with glutamate receptor antagonists CNQX (10 μM) and AP-5 (50 μM), and were markedly reduced in a Ca 2+ -free Krebs solution; the differences were statistically significant. Tat30-86-induced inward currents had a reversal potential between -30 and 0 mV. While not causing a noticeable depolarization, lower concentrations of Tat30-86 (10 nM) increased membrane excitability, as indicated by increased numbers of neuronal discharge in response to a step depolarizing pulse. Tat30-86 (10 nM) increased the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), while not significantly affecting their amplitude. Tat30-86 (10 nM) moderately increased the frequency as well as the amplitude of spontaneous miniature inhibitory postsynaptic currents (mIPSCs). Ratiometric Ca 2+ imaging studies showed that Tat30-86 produced three types of Ca 2+ responses: 1) a fast and transitory increase, 2) Ca 2+ oscillations, and 3) a fast increase followed by a plateau; the glutamate receptor antagonists eliminated the late component of Ca 2+ response. The result suggests that Tat30-86 is an active fragment and that it excites cortical neurons directly and indirectly via releasing glutamate from adjacent neurons. Keywords calcium imaging; electrophysiology; postsynaptic currentsInfection of the central nervous system (CNS) with the human immunodeficiency virus 1 (HIV-1) may lead to cognitive, motor and behavioral dysfunctions, collectively termed HIVCorresponding author: G. Cristina Brailoiu, M.D., Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, PA 19140 USA, Tel: 215-707-7705, Fax: 215-707-7068, E-mail: gbrailou@temple.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Kaul et al., 2001; Gonzales-Scara...

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Section: Discussionmentioning

confidence: 99%

Section: Abstract Calcium Imaging; Electrophysiology; Postsynaptic Cumentioning

confidence: 98%

mentioning

confidence: 96%

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Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons

et al. 2008

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“…On the other hand, viral proteins can also have effects. Tat has been found to reset the circadian rhythm of spontaneous action potentials recorded in the SCN and to affect the circadian rhythm of the wheel-running activity in mice (31). The surface envelope protein gp120 causes a significant reduction in glucose utilization in the SCN (32).…”

Section: Fig 3 Effects Of Siv Infection On the Circadian Rhythm Of mentioning

confidence: 99%

Effects of simian immunodeficiency virus on the circadian rhythms of body temperature and gross locomotor activity

Huitrón‐Reséndiz

Marcondes

Flynn

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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In monkeys infected with simian immunodeficiency virus (SIV), changes in body temperature and locomotor activity occur after the acute retroviral syndrome stage of the disease. However, alterations to the circadian rhythm of these factors in SIV-infected monkeys have not been reported. To determine whether the circadian rhythm of body temperature and locomotor activity are disrupted during SIV infection, we analyzed the temperature and activity patterns of SIV-infected monkeys through different stages of the disease, progressing to SIV encephalitis by using the cosinor model for circadian oscillation. We found that SIV infection resulted in significant impairments of the amplitude and mean of the circadian rhythm of body temperature and activity and in the acrophase of the circadian rhythm for temperature. These alterations were not related to changes observed in the acute febrile response induced after viral inoculation. In animals killed once marked circadian anomalies were evident, microglia infiltration and macrophage accumulation in the hypothalamus were observed. Together, these results clearly demonstrate that SIV infection compromises aspects of circadian regulation in monkeys, with important implications for physiological functions, including cognition, in HIV-infected individuals.AIDS ͉ CNS ͉ dementia ͉ HIV

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“…According to previously published methods, C57B/6 mice (Harlan, Indianapolis, IN), 14 -21 days old, were entrained to a 12-h light:12-h dark cycle (LD) in colony chambers with unrestricted access to food and water (Clark et al 2005). Mice were killed using a guillotine to avoid altering immediate early gene expression and circadian rhythms caused by standard anesthesia (pentobarbital, isoflurane, propofol, CO 2 , urethan, chloralose, and halothane) (Prosser et al 1994;Sica et al 1999;Takayama et al 1994).…”

Section: Electrophysiological Recordingsmentioning

confidence: 99%

Stoichiometry ofN-Methyl-d-Aspartate Receptors Within the Suprachiasmatic Nucleus

Clark

Kofuji²

2010

Journal of Neurophysiology

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Clark JP, Kofuji P. Stoichiometry of N-methyl-D-aspartate receptors within the suprachiasmatic nucleus. J Neurophysiol 103: 3448 -3464, 2010. First published April 21, 2010 doi:10.1152/jn.01069.2009. The circadian pacemaker within the suprachiasmatic nucleus (SCN) confers daily rhythms to bodily functions. In nature, the circadian clock will adopt a 24-h period by synchronizing to the solar light/dark cycle. This light entrainment process is mediated, in part, at glutamatergic synapses formed between retinal ganglion afferents and SCN neurons. N-methyl-D-aspartate receptors (NMDARs) located on SCN neurons gate light-induced phase resetting. Despite their importance in circadian physiology, little is known about their functional stoichiometry. We investigated the NR2-subunit composition with whole cell recordings of SCN neurons within the murine hypothalamic brain slice using a combination of subtype-selective NMDAR antagonists and voltageclamp protocols. We found that extracellular magnesium ([Mg] o ) strongly blocks SCN NMDARs exhibiting affinities and voltage sensitivities associated with NR2A and NR2B subunits. These NMDAR currents were inhibited strongly by NR2B-selective antagonists, Ro 25-6981 (3.5 M, 55.0 Ϯ 9.0% block; mean Ϯ SE) and ifenprodil (10 M, 55.8 Ϯ 3.0% block). The current remaining showed decreased [Mg] o affinities reminiscent of NR2C and NR2D subunits but was highly sensitive to [Zn] o , a potent NR2A blocker, showing a ϳ44.2 Ϯ 1.1% maximal inhibition at saturating concentrations with an IC 50 of 7.8 Ϯ 1.1 nM. Considering the selectivity, efficacy, and potency of the drugs used in combination with [Mg] oblock characteristics of the NMDAR, our data show that both diheteromeric NR2B NMDARs and triheteromeric NR2A NMDARs (paired with an NR2C or NR2D subunits) account for the vast majority of the NMDAR current within the SCN. I N T R O D U C T I O NThe suprachiasmatic nucleus (SCN) of the hypothalamus generates a daily rhythm that is reflected in behavioral and bodily functions. The properties of this rhythm are determined in large part by the molecular machinery of neurons that form an oscillating cellular network within the SCN (Herzog 2007). In mammals, this circadian rhythm synchronizes to the environmental light-dark cycles through a direct pathway from the retina to the SCN, the retinohypothalamic tract (Johnson et al. 1988). During this light entrainment process, light depolarizes retinal ganglion cells that express the photopigment, melanopsin, which, in turn, releases glutamate from their terminals at synapses formed with neurons of the SCN Hattar et al. 2002).L-glutamate is the primary neurotransmitter of the retinohypothalamic tract and is required for the entrainment of the circadian pacemaker to the solar light-dark cycle (Hannibal 2002). Although, ionotropic glutamate receptors of the SCN, N-methyl-D-aspartate receptors (NMDARs) and amino-methyl proprionic acid/kainate receptors, participate in this process (Colwell and Menaker 1992;Ebling 1996), NMDAR activation is necessary a...

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HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

Cited by 29 publications

References 47 publications

Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons

Excitatory effects of human immunodeficiency virus 1 Tat on cultured rat cerebral cortical neurons

Effects of simian immunodeficiency virus on the circadian rhythms of body temperature and gross locomotor activity

Stoichiometry ofN-Methyl-d-Aspartate Receptors Within the Suprachiasmatic Nucleus

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