Endogenous TRPV1 expression in the human cingulate- and medial frontal gyrus
Introduction
TRPV1 is a subfamily of the transient receptor potential cation channels and functions as a molecular integrator for multiple types of sensory input. It is selective for calcium ions and responds to capsaicin, noxious heat, low extracellular pH, divalent cations, and particular toxins (Yang and Zheng, 2017). TRPV1 has been described in the peripheral pain pathway where the receptor can initiate nociceptive signaling by generating a receptor potential (Premkumar and Sikand, 2008). In addition to peripheral expression, various reports state that TRPV1 can be found in the brain (Marrone et al., 2017). Recently, TRPV1 was used as an actuator for neuromodulation in mouse brain (Chen et al., 2015). However, due to low endogenous expression of TRPV1 in the central nervous system of rodents, the TRPV1 channel was introduced with lentiviral delivery. This method of neuromodulation seems to be a promising approach for future clinical application, although lentiviral delivery of TRPV1 might be undesirable.
To explore the possible clinical use of TRPV1 for neuromodulation we investigated if TRPV1 is endogenously expressed in the human brain. A sufficient expression of TRPV1 in neurons is necessary for this technique to work properly. We focused on subjects with depression since TRPV1 channels have been implicated in depression and anxiety (Madasu et al., 2015; Marsch et al., 2007; Wang et al., 2017; Sartim et al., 2019; Reyes-Mendez et al., 2018).
We investigated the MFG and CG of subjects whom experienced depression in their medical histories and compared them to non-demented control subjects. The MFG, which is part of the dorsolateral prefrontal cortex, is hypoactive in MDD while the CG is hyperactive in MDD (Mayberg et al., 2005; Koenigs and Grafman, 2009). Therefore, these brain regions are potential targets for neuromodulation. In this article, we aim to examine whether TRPV1 is sufficiently expressed in these brain regions to be considered as a target for neuromodulation.
Section snippets
Subjects
Fresh-frozen and paraffin embedded brain tissue of depressed and control subjects containing the CG and MFG were provided by the Netherlands Brain Bank (NBB) (Table 1). As a positive control, we used temporal neocortical tissue of an epileptic patient provided by Maastricht UMC+ (MUMC+) for an abundant expression of TRPV1 in patients with mesial temporal lobe epilepsy has been reported earlier (Sun et al., 2013). All experiments have been carried out in accordance with The Code of Ethics of the
Western blotting
Results showed an immunoreactive band of 95 kDa in control tissue and the MFG and CG in both depressed and control subjects (Fig. 1 and supplementary Fig. 1).
Pre-absorption of the anti-TRPV1 antibody with synthetic peptide resulted in a loss of the 95 kDa immunoreactive band. In addition, this condition also resulted in the loss of several lower immunoreactive bands (supplementary Figs. 2 and 3). Analysis of the OD showed a high inter-individual variability of the 95 kDa immunoreactive band and
Discussion
In the present study we showed that the TRPV1 channel was expressed in both the CG and MFG of subjects with a history of depression as well as controls. No differences in TRPV1 expression levels were found between the depression and control groups. However, strong inter-individual differences in TRPV1 expression level were detected. Immunohistochemistry revealed TRPV1 expression in morphologically glial-like cells, endothelial cells, neurites, and neurons. In addition, fluorescent double
Conclusion
This study showed that TRPV1 is present in the human CG and MFG in both depressed and control subjects. TRPV1 expression levels differ between subjects and do not seem to be dependent on depression in one’s medical history. TRPV1 expression was extensively co-localized with GFAP indicating its abundant expression in astrocytes. Since neuronal TRPV1 expression is scarce, the potential use of TRPV1 for neuromodulation seems restricted. Interestingly, glial expression of TRPV1 may indicate an
Declaration of Competing Interest
All authors declare to have no conflict of interest.
Acknowledgements
The authors thank the neurosurgeon Jim T. A. Dings and the Netherlands Brain Bank for providing brain tissue as well as Frédéric L.W.V.J. Schaper, Hellen P. J. Steinbusch for their technical support; and Jackson T. Boonstra for English editing. This work was supported and funded by the school for Mental Health and Neuroscience (MHeNS) of the University of Maastricht (UM).
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