Inhibitory Control Deficits Associated with Upregulation of CB1R in the HIV-1 Tat Transgenic Mouse Model of Hand

Abstract

In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indirectly via its actions on glia. The Go/No-Go (GNG) task was used to examine HAND in the Tat transgenic mouse model. The GNG task involves subjects discriminating between two stimuli sets in order to determine whether or not to inhibit a previously trained response. Data reveal inhibitory control deficits in female Tat(+) mice (p = .048) and an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB1R expression (r = −.543, p = .045), with CB1R expression predicting 30% of the variance of inhibitory control (R2 = .295, p = .045). Furthermore, there was a significant increase in spontaneous excitatory postsynaptic current (sEPSC) frequencies in Tat(+) compared to Tat(−) mice (p = .008, across sexes). The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001). Overall, the GNG task is a viable measure to assess inhibitory control deficits in Tat transgenic mice and results suggest a potential therapeutic treatment for the observed deficits with drugs which modulate endocannabinoid enzyme activity.

Chronic HIV-1 Tat exposure alters anterior cingulate cortico-basal ganglia-thalamocortical synaptic circuitry, associated behavioral control, and immune regulation in male mice

“…Accordingly, Tat-induced dysregulation of the ACC, striatum, and thalamus may result in decreased control of novelty-exploration, adaptability, and pre-attentive filtering. Although previous findings indicate ~1 month of Tat exposure increases PFC excitatory postsynaptic currents ( Jacobs et al, 2019 ; Xu et al, 2017 ), the 8 weeks of Tat exposure in the current study did not affect the spine density, length, or branching of ACC layer V pyramidal neuronal dendrites. This disparity may relate to, (i) Tat-induced reductions in KCC2 ( Barbour et al, 2020 ) altering chloride concentrations and reducing GABA potency, (ii) increased excitatory postsynaptic potentials preceding changes in dendritic spine density or dendritic complexity, which are likely to be altered with more prolonged Tat exposure, and (iii) in one instance, a difference in the model (rats) and Tat exposure (added acutely to PFC ex vivo slices) ( Wayman et al, 2015 ).…”

HIV Tat Protein Selectively Impairs CB1Receptor-Mediated Presynaptic Inhibition at Excitatory But Not Inhibitory Synapses

“…Thus, the network effects of D 9 -THC could shift to an excitatory response due to CB 1 R-mediated suppression of GABA release without a corresponding decrease in glutamate release. This prediction is consistent with the increased miniature EPSC frequency observed in mice expressing Tat (Jacobs et al, 2019).…”

“…In contrast to the loss of CB 1 R function described here, CB 1 R protein increased in infralimbic cortex from transgenic mice expressing Tat (Jacobs et al, 2019). The mPFC and hippocampus display differential sensitivity to Tat (Cirino et al, 2020), suggesting the effects of Tat on the eCB system may also exhibit regional differences.…”

“…Interestingly, eCB modulation of glutamatergic transmission was not affected in this model, setting a precedent for differential modulation of eCB signaling at inhibitory versus excitatory synapses under neuroinflammatory conditions. In transgenic mice expressing HIV Tat, CB 1 Rs are upregulated (Jacobs et al, 2019); whether this increase preferentially affects GABAergic neurons is unclear.…”

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

“…Thus, CB1 signaling could function as a feedback mechanism to control tat-induced excitotoxicity in prefrontal cortex neurons. The same group reported that CB1 receptors are upregulated in neurons of the prelimbic prefrontal cortex in female tat-transgenic mice [ 119 ], suggesting that this system may be sex-specific. However, a new study examining cultured rat hippocampal neurons reported that tat treatment prevents CB1-mediated presynaptic inhibition at excitatory synapses, but does not affect inhibitory synapses, suggesting that CB1-mediated neuroprotection may not extend to the hippocampus [ 120 ].…”