Inhibitory Neurotransmission Is Sex-Dependently Affected by Tat Expression in Transgenic Mice and Suppressed by the Fatty Acid Amide Hydrolase Enzyme Inhibitor PF3845 via Cannabinoid Type-1 Receptor Mechanisms
Changqing Xu,
Barkha J. Yadav-Samudrala,
Callie Xu,
Bhupendra Nath,
Twisha Mistry,
Wei Jiang,
Micah J. Niphakis,
Benjamin F. Cravatt,
Somnath Mukhopadhyay,
Aron H. Lichtman,
Bogna M. Ignatowska-Jankowska,
Sylvia Fitting
Affiliations
Changqing Xu
Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Barkha J. Yadav-Samudrala
Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Callie Xu
Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Bhupendra Nath
Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC 27707, USA
Twisha Mistry
Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC 27707, USA
Wei Jiang
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
Micah J. Niphakis
Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
Benjamin F. Cravatt
Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
Somnath Mukhopadhyay
Department of Chemistry & Biochemistry, North Carolina Central University, Durham, NC 27707, USA
Aron H. Lichtman
Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
Bogna M. Ignatowska-Jankowska
Neuronal Rhythms in Movement Unit, Okinawa Institute of Science and Technology, Onna 904-0495, Japan
Sylvia Fitting
Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
(1) Background. The endocannabinoid (eCB) system, which regulates physiological and cognitive processes, presents a promising therapeutic target for treating HIV-associated neurocognitive disorders (HAND). Here we examine whether upregulating eCB tone has potential protective effects against HIV-1 Tat (a key HIV transactivator of transcription) protein-induced alterations in synaptic activity. (2) Methods. Whole-cell patch-clamp recordings were performed to assess inhibitory GABAergic neurotransmission in prefrontal cortex slices of Tat transgenic male and female mice, in the presence and absence of the fatty acid amide hydrolase (FAAH) enzyme inhibitor PF3845. Western blot and mass spectrometry analyses assessed alterations of cannabinoid receptor and enzyme protein expression as well as endogenous ligands, respectively, to determine the impact of Tat exposure on the eCB system. (3) Results. GABAergic activity was significantly altered upon Tat exposure based on sex, whereas the effectiveness of PF3845 to suppress GABAergic activity in Tat transgenic mice was not altered by Tat or sex and involved CB1R-related mechanisms that depended on calcium signaling. Additionally, our data indicated sex-dependent changes for AEA and related non-eCB lipids based on Tat induction. (4) Conclusion. Results highlight sex- and/or Tat-dependent alterations of GABAergic activity and eCB signaling in the prefrontal cortex of Tat transgenic mice and further increase our understanding about the role of FAAH inhibition in neuroHIV.
