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CANNABINOIDS ARE NEUROPROTECTIVE AGAINST HIV‐1 TAT AND OCCLUDE THE TAT‐INDUCED DECREASE IN GABAERGIC NEUROTRANSMISSION IN PREFRONTAL CORTEX SLICES
Author(s) -
Xu Changqing,
Hermes Douglas J,
Mackie Ken,
Lichtman Aron H,
IgnatowskaJankowska Bogna M,
Fitting Sylvia
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.705.7
Subject(s) - neuroprotection , neurotransmission , cannabinoid receptor , cannabinoid , endocannabinoid system , neuroscience , inhibitory postsynaptic potential , gabaergic , pharmacology , postsynaptic potential , chemistry , prefrontal cortex , medicine , biology , receptor , agonist , biochemistry , cognition
In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV‐1) is now considered a chronic disease that specifically targets the brain and causes a high prevalence of mild forms of neurocognitive impairments, also referred to as HIV‐associated neurocognitive disorders (HAND). HAND is due in part to defects in synaptic neurotransmission that leads to synaptodendritic injury, including damage to synapses and dendrites. Endocannabinoids have been suggested to protect central nervous system (CNS) neurons in different disease models of toxicity, but their effect in HAND are poorly known. To address this issue primary prefrontal cortex (PFC) neuron culture studies examined the neuroprotective effects of the synthetic cannabinoid WIN55,212‐2 and the endocannabinoid N‐arachidonoyl ethanolamine (anandamide/AEA) on HIV‐1 Tat excitotoxicity and neuronal survival. Data demonstrated that WIN55,212‐2 and AEA are protective against HIV‐1 Tat‐induced increases in [Ca 2+ ] i as well as neuron injury and cell death via a cannabinoid 1 receptor (CB 1 R)‐mediated mechanism. Further, whole‐cell patch‐clamp recordings were performed on PFC slices to assess cannabinoid effects on GABAergic neurotransmission in the presence of HIV‐1 Tat. Results indicated a HIV‐1 Tat concentration dependent (5 – 50 nM) decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) but not spontaneous IPSCs (sIPSCs). Zero external calcium and cadium chloride (CdCl 2 , 200 μM), which blocks high and low threshold voltage‐dependent calcium currents, prevented the significant Tat‐induced decrease in mIPSCs. Interestingly, bath‐applied WIN55,212‐2 or AEA that significantly decreased the frequency but not amplitude of mIPSCs and/or spontaneous IPSCs (sIPSCs) blocked a further down‐regulation of IPSCs by Tat. Lastly, pretreatment with SR141716A, a CB 1 R antagonist, prevented the AEA‐induced decrease in IPSCs frequency without any further Tat effect. These results suggest that Tat significantly decreases GABAergic neurotransmission at the level of an action potential‐independent release of GABA due to the influx of extracellular calcium, partially via voltage‐dependent calcium currents. Additionally, bath application of cannabinoids following or prior Tat treatment occluded the Tat‐induced decrease in GABA release, with cannabinoids acting via a CB 1 R‐related mechanism. Understanding the effects of cannabinoids in the context of neuro AIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur. Support or Funding Information NIDA R00 DA033878, T32 DA007244