Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy?

Zhou, Yan; Tang, Hongmei; Xiong, Huangui

doi:10.1007/s11481-016-9660-2

Cited by 17 publications

(20 citation statements)

References 45 publications

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“…Studies in animal models confirmed that alcohol induces elevated expression of CCL2 in the CNS (see Introduction). CCL2 has been shown to have neuronal actions in experimental preparations (Qin et al, 2005; van Gassen et al, 2005; Cho and Gruol, 2008; Edman et al, 2008; Jung et al, 2008; Guyon et al, 2009; You et al, 2010; Belkouch et al, 2011; Kao et al, 2012; Zhou et al, 2016). These findings raise the possibility that effects of CCL2 may play a role in the CNS actions of alcohol.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

2017

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Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine CCL2. The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated. Our studies focus on the hypothesis that increased levels of CCL2 in the CNS produce neuroadaptive changes that modify the actions of alcohol on the CNS. We utilized behavioral testing in transgenic mice that express elevated levels of CCL2 to test this hypothesis. The increased level of CCL2 in the transgenic mice involves increased astrocyte expression. Transgenic mice and their non-transgenic littermate controls were subjected to one of two alcohol exposure paradigms, a two-bottle choice alcohol drinking procedure that does not produce alcohol dependence or a chronic intermittent alcohol procedure that produces alcohol dependence. Several behavioral tests were carried out including the Barnes Maze, Y-Maze, cued and contextual conditioned fear test, light-dark transfer, and forced swim test. Comparisons between alcohol naïve, non-dependent, and alcohol dependent CCL2 transgenic and non-tg mice show that elevated levels of CCL2 in the CNS interact with alcohol in tests for alcohol drinking, spatial learning and associative learning.

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Section: Discussionmentioning

confidence: 99%

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

2017

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“…The production of CCL2 by neurons during acute encephalitis may play a role in more than just leukocyte recruitment. For example, hippocampal neurons express CCR2 [21] and CCL2 directly enhances both NMDA receptor-and AMPA receptor-mediated excitatory postsynaptic potentials [30]. This suggests that the earliest stages of hippocampal circuit dysregulation associated with acute TMEV infection may be triggered locally by neuronal CCL2 acting in a autocrine fashion [31,32].…”

Section: Discussionmentioning

confidence: 99%

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Howe

LaFrance‐Corey

Goddery

et al. 2017

Preprint

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Background: Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler's murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear. Methods: Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2. Results: Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 hours postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain. Conclusions: We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.

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“…However, it is important to note that HIV also affects many other ion channels and receptors that likely participate in pathogenic processes related to HAND and that may also be affected in the current model/treatment regimen. For example, HIV reduces inhibitory GABA neurotransmission (Buzhdygan et al, 2016) and enhances the activity of another ionotropic glutamate receptor, the AMPAR (Epstein, 1998; Zhou et al, 2016). Reduced inhibitory neurotransmission (GABA) and increased excitatory stimulation of glutamatergic ionotropic receptors (AMPA and NMDAR) also contributes to membrane depolarizations that, if large enough, could ultimately activate VGCCs, including the L-channel, and promote excessive Ca 2+ influx.…”

Section: Discussionmentioning

confidence: 99%

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Khodr

Chen

Davé

et al. 2016

Neurobiology of Disease

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Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca2+ channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca2+ potentials (Ca2+ influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K+ influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca2+ influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca2+ potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca2+ influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca2+ dysregulation in the mPFC.

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Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy?

Cited by 17 publications

References 45 publications

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

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