NMDARs adapt to neurotoxic HIV protein tat downstream of a GluN2A–ubiquitin ligase signaling pathway

Matthew V. Green, Stanley A Thayer

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Infected non-neuronal cells release neurotoxic factors such as the viral protein transactivator of transcription (Tat) that potentiate NMDAR function. NMDARs regulate synaptic changes observed after exposure to HIV proteins, which may underlie cognitive impairment in HAND patients. Here, we used patch-clamp recording to measure NMDAR-mediated currents in rat hippocampal cultures after exposure to Tat. Tat (4 –16 h) potentiated NMDA-evoked whole-cell current and increased the NMDAR: AMPAR ratio of evoked EPSCs. Potentiated currents adapted back to baseline amplitudes after 24 h of exposure to Tat. Pharmacological inhibition of GluN2A-containing NMDARs prevented adaptation, but inhibition of GluN2B-containing NMDARs did not. Pharmacological and genetic approaches determined that potentiated NMDARs activated the kinase Akt, which then activated the E3 ubiquitin ligase Mdm2. Inhibition of protein synthesis prevented adaptation, suggesting that Mdm2 altered gene expression, possibly through its well known target p53. Expression of GFP-tagged GluN1 subunits resulted in fluorescent puncta that colocalized with synaptic markers. Tat (24 h) caused an Mdm2-dependent loss of NMDAR puncta on a timescale similar to adaption of NMDAR function. Activation of theMdm2pathway degrades PSD-95, a scaffolding protein that clusters NMDAR sat the synapse and enhances their function. Adaptation to the continued presence of excitotoxins that potentiate NMDARs such as HIV Tat may protect from excessive NMDAR activation while also contributing to the synaptic loss that correlates with cognitive decline in HAND.

Original languageEnglish (US)
Pages (from-to)12640-12649
Number of pages10
JournalJournal of Neuroscience
Volume36
Issue number50
DOIs
StatePublished - Dec 14 2016

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (National Institute on Drug Abuse Grant DA07304 to S.A.T. and Training Grant T32DA07234 to M.V.G.).

Keywords

  • Akt
  • GluN2A
  • GluN2B
  • HIV Tat
  • MDM2
  • NMDAR

Fingerprint Dive into the research topics of 'NMDARs adapt to neurotoxic HIV protein tat downstream of a GluN2A–ubiquitin ligase signaling pathway'. Together they form a unique fingerprint.

Cite this