The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Górska, Anna; Eugenín, Eliseo A.

doi:10.3389/fcimb.2020.00261

Cited by 41 publications

(32 citation statements)

References 278 publications

(401 reference statements)

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“…Glutamate is the main neurotransmitter involved in cognitive functions in the frontal cortex and hippocampus. In previous research, the levels of glutamate were found to be decreased with other viral infections of the CNS, such as HIV-related dementia [8] which has been associated with metabolic derangement [9] . Congruently, Crunfli et al have suggested that the redeployment of metabolism in SARS-CoV-2-infected astrocytes may be associated with a disruption within the glutamatergic pathway.…”

Section: Discussionmentioning

confidence: 92%

COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway

Yeşilkaya

Sen

Balcıoğlu

2021

Journal of Clinical Neuroscience

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Cognitive impairment has recently attracted researchers as one of the possible neuropsychiatric manifestations of COVID-19, although how the infection perpetuates impairment of cognitive functions is still obscure. We presented a 29-year-old male patient with COVID-19 who developed new-onset transient attention deficit and memory problems following a SARS-CoV-2 infection. Structural neuroimaging was normal. MR-spectroscopy (MRS) of the bilateral DLPFC revealed significant for decreased levels of N-acetylaspartate (NAA), glutamate, and glutamate/glutamine ratio. After a follow-up without any medical treatment but with suggestions of memory exercises for three months a control MRS screening of DLPFC showed improved levels of NAA, glutamate, and glutamate/glutamine ratio. This report may suggest that cognitive deficits in SARS-CoV-2 infection can result from glutamatergic dysfunction with decreased NAA and glutamate levels in bilateral DLPFC.

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Section: Discussionmentioning

confidence: 92%

COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway

Yeşilkaya

Sen

Balcıoğlu

2021

Journal of Clinical Neuroscience

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Section: Neuroimaging and Neuropathological Studies In Hand Patientsmentioning

confidence: 99%

“…Dysregulated inhibitory circuits may also lead to abnormal excitatory neurotransmission via the glutamate system, which has long been reported in HAND patients and models [ 64 ]. However, clinical studies of brain glutamate levels in HAND have reported conflicting results, which likely reflects the underlying complexity of HAND in different patients [ 64 ]. While there is evidence that ART can decrease extracellular glutamate levels in the brain [ 65 ], many studies in model systems have demonstrated that HIV proteins may directly and indirectly enhance glutamatergic signaling [ 66 , 67 ].…”

Section: Neuroimaging and Neuropathological Studies In Hand Patientsmentioning

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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“…An increase in the level of extracellular glutamate, which is considered to be one of the major causes of neuronal toxicity in HIV-1 patients ( Gorska & Eugenin, 2020 ). To assess whether alterations in glutamate levels are critical for the astrocyte-mediated neuronal damage, and to deduce whether the increase in the level of extracellular glutamate has any effects on neuronal death, we performed a TUNEL assay on neurons.…”

Section: Resultsmentioning

confidence: 99%

Role of EphrinA3 in HIV-1 Neuropathogenesis

et al. 2021

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Glial cells perform important supporting functions for neurons through a dynamic crosstalk. Neuron–glia communication is the major phenomenon to sustain homeostatic functioning of the brain. Several interactive pathways between neurons and astrocytes are critical for the optimal functioning of neurons, and one such pathway is the ephrinA3–ephA4 signaling. The role of this pathway is essential in maintaining the levels of extracellular glutamate by regulating the excitatory amino acid transporters, EAAT1 and EAAT2 on astrocytes. Human immunodeficiency virus-1 (HIV-1) and its proteins cause glutamate excitotoxicity due to excess glutamate levels at sites of high synaptic activity. This study unravels the effects of HIV-1 transactivator of transcription (Tat) from clade B on ephrinA3 and its role in regulating glutamate levels in astrocyte–neuron co-cultures of human origin. It was observed that the expression of ephrinA3 increases in the presence of HIV-1 Tat B, while the expression of EAAT1 and EAAT2 was attenuated. This led to reduced glutamate uptake and therefore high neuronal death due to glutamate excitotoxicity. Knockdown of ephrinA3 using small interfering RNA, in the presence of HIV-1 Tat B reversed the neurotoxic effects of HIV-1 Tat B via increased expression of glutamate transporters that reduced the levels of extracellular glutamate. The in vitro findings were validated in autopsy brain sections from acquired immunodeficiency syndrome patients and we found ephrinA3 to be upregulated in the case of HIV-1-infected patients. This study offers valuable insights into astrocyte-mediated neuronal damage in HIV-1 neuropathogenesis.

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The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Cited by 41 publications

References 278 publications

COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway

COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Role of EphrinA3 in HIV-1 Neuropathogenesis

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