HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat. Here, we tested the hypothesis that Tat-induced loss and ifenprodil-mediated rescue of synaptic spines in vivo would predict impairment and rescue of cognitive function. Using intracranial multiphoton imaging, we found that infusion of 100 ng of HIV-1 Tat into the lateral ventricle of yellow fluorescent protein-expressing transgenic mice produced a 17 ± 1% loss of dendritic spines in layer 1 of retrosplenial cortex. Repeated imaging of the same dendrites over 3 weeks enabled longitudinal experiments that demonstrated sustained spine loss after Tat infusion and transient rescue after ifenprodil administration (10 mg/kg, i.p.). Parallel trace fear conditioning experiments showed that spine loss predicted learning deficits and that the time course of ifenprodil-induced rescue of spine density correlated with restoration of cognitive function. These results show for the first time that, during exposure to an HIV-1 neurotoxin in vivo, alteration of GluN2Bcontaining NMDAR signaling suppresses spine density and impairs learning. Pharmacological inhibition of these NMDARs rescued spines and restored cognitive function. Drugs that rescue synapses may improve neurocognitive function in HAND.
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Received Jan. 24, 2017; revised May 18, 2017; accepted July 7, 2017. Authorcontributions:J.D.R.,N.J.H.,andS.A.T.designedresearch;J.D.R.andN.J.H.performedresearch;J.D.R.and S.A.T. analyzed data; J.D.R. and S.A.T. wrote the paper. This work was supported by the National Institutes of Health (National Institute on Drug Abuse Grants DA07304 and DA035663 to SAT). Multiphoton imaging was conducted with support of the University Imaging Centers at the UniversityofMinnesota.WethankDr.GuillermoMarquesforhelpindesigningtheimagingassay;Drs.MarkThomas and Michael Benneyworth for helpful discussions regarding behavior experiments; and Mustafa Mithaiwala and Ansel Shuster for assistance with colony maintenance and data quantification. The authors declare no competing financial interests. N.J. Hargus’s present address: Cardiovascular Systems, Inc., Saint Paul, MN 55112. Correspondence should be addressed to S.A. Thayer, Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street S.E., Minneapolis, MN 55455. E-mail: email@example.com.
- Dendritic spines
- HIV neurotoxicity
- Multiphoton imaging