Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat

A. H. Shin, H. J. Kim, S. A. Thayer

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

BACKGROUND AND PURPOSE Neurocognitive disorders afflict approximately 20% of HIV-infected patients. HIV-1-infected cells in the brain shed viral proteins such as transactivator of transcription (Tat). Tat elicits cell death and synapse loss via processes initiated by NMDA receptor activation but mediated by separate downstream signalling pathways. Subunit selective NMDA receptor antagonists may differentially modulate survival relative to synaptic changes. EXPERIMENTAL APPROACH Tat-evoked cell death was quantified by measuring propidium iodide uptake into rat hippocampal neurons in culture. The effects of Tat on synaptic changes were measured using an imaging-based assay that quantified clusters of the scaffolding protein postsynaptic density 95 fused to green fluorescent protein. KEY RESULTS Dizocilpine, a non-competitive NMDA receptor antagonist, inhibited Tat-induced synapse loss, subsequent synapse recovery and Tat-induced cell death with comparable potencies. Memantine (10 μM) and ifenprodil (10 μM), which preferentially inhibit GluN2B-containing NMDA receptors, protected from Tat-induced cell death with no effect on synapse loss. Surprisingly, memantine and ifenprodil induced synapse recovery in the presence of Tat. In contrast, the GluN2A-prefering antagonist TCN201 prevented synapse loss and recovery with no effect on cell death. CONCLUSIONS AND IMPLICATIONS Synapse loss is a protective mechanism that enables the cell to cope with excess excitatory input. Thus, memantine and ifenprodil are promising neuroprotective drugs because they spare synaptic changes and promote survival. These GluN2B-preferring drugs induced recovery from Tat-evoked synapse loss, suggesting that synaptic pharmacology changed during the neurotoxic process. NMDA receptor subtypes differentially participate in the adaptation and death induced by excitotoxic insult.

Original languageEnglish (US)
Pages (from-to)1002-1017
Number of pages16
JournalBritish Journal of Pharmacology
Volume166
Issue number3
DOIs
StatePublished - Jun 2012

Keywords

  • HIV Tat
  • HIV-associated neurocognitive disorders (HAND)
  • NMDA receptor
  • TCN201
  • dizocilpine
  • ifenprodil
  • memantine
  • neurotoxicity
  • synapse loss
  • synapse recovery

Fingerprint Dive into the research topics of 'Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat'. Together they form a unique fingerprint.

  • Cite this