Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula
Introduction
Schizophrenia is a highly complex, multifactorial illness involving multiple genetic and environmental factors. Microstructurally, schizophrenia manifests itself in deficits in neuron number and architecture, disturbed neural circuits, wide-spread glial cell abnormalities and certain immune/inflammatory changes (for recent reviews, see Bernstein et al., 2015, Falkai et al., 2015, Khandaker et al., 2015). However, during the past two decades a good body of evidence has accumulated that microvascular abnormalities and malfunction of the blood–brain barrier (BBB) might also significantly contribute to schizophrenia pathophysiology (Müller and Ackenheil, 1995, Rothermund et al., 2004, Hanson and Gottesman, 2005, Harris et al., 2008, Kreczmanski et al., 2009, Uranova et al., 2010, Piontkewitz et al., 2012, Schoknecht and Shalev, 2012, Sinka et al., 2012, Meier et al., 2013, Wright et al., 2014, Lopes et al., 2015, Vetter et al., 2015). An important molecular component of the BBB, which is expressed in most (if not all) brain capillary endothelial cells with a developed BBB (Bernstein et al., 2014), is the ATP-binding cassette sub-family B member 1 (ABCB1; aka P-glycoprotein 1, MDR1 — multidrug resistance protein 1, or CD 243). ABCB1 is a 170 kDa protein, which functions as an potent and efficient efflux pump extruding multiple drugs, xenobiotics, and metabolites from brain capillaries, the choroid plexus cells, and the brain interstitial fluid/cerebrospinal fluid into the blood stream, thus playing a pivotal role in the detoxification, neuroprotection, neurodegeneration, and overall central nervous system (CNS) homeostasis (for overviews, see Pahnke et al., 2008, Bundgaard et al., 2012, Miller, 2015). ABCB1 is therefore regarded as a “major gatekeeper” of the brain (Thoeringer et al., 2007). ABCB1 has been implicated in a number of neurodegenerative and psychiatric disorders, including schizophrenia (for recent reviews, see Pahnke et al., 2014, Hoosain et al., 2015). ABCB1 activity hampers the brain uptake of most (not all) antipsychotic drugs, with risperidone having the strongest affinity to ABCB1 (reviewed in De Klerk et al., 2010, Bundgaard et al., 2012). Moreover, ABCB1 gene polymorphisms have repeatedly been shown to be associated with schizophrenia, influencing drug response and antipsychotic-induced metabolic disturbances in schizophrenia (Qian et al., 2006, Wang et al., 2006, De Klerk et al., 2010, Kuzman et al., 2011, Yoo et al., 2011, Crisafulli et al., 2012, Lee et al., 2012, Vijayan et al., 2012, Suzuki et al., 2013 and others), Hence, by-passing ABCB1 has recently been proposed as a therapeutic option in treatment-resistant schizophrenia (Bebawy and Chetty, 2008, Hoosain et al., 2015). However, in face of its potential impact for the disease, amazingly little is known about the expression and/or activity of ABCB1 in schizophrenia. De Klerk et al. (2010) performed a PET study with ten medicated patients suffering from chronic paranoid schizophrenia, using [11C] verapamil as a radiochemical probe for ABCB1 function. Compared with controls a regional increase in ABCB1 function was revealed in schizophrenia patients. However, using the same radiotracer verapamil, it was recently shown that acute antipsychotic treatment of rats decreased brain ABCB1 activity (Doorduin et al., 2014). The paucity of information on the regional and cellular expression of ABCB1 protein in schizophrenia prompted to study this protein immunohistochemically in twelve brain regions known to play prominent roles in schizophrenia (left and right posterior cingulate cortex: Wang et al., 2015; left and right inferior temporal cortex, Knöchel et al., 2016; left and right inferior temporal cortex: Nenadic et al., 2015; left and dentate gyrus: Haukvik et al., 2015; left and right habenula: Stopper and Floresco, 2015 and left and right temporal white matter: Wheeler and Voineskos, 2014).
Section snippets
Post-mortem human brain tissue
All brains were obtained from the Magdeburg brain bank at the University Department of Psychiatry. The case recruitment, acquisition of personal data, performance of autopsy, and handling of autoptic material were conducted in accordance with the Declaration of Helsinki and were approved by the Ethics Committee of Magdeburg University. Written consent was obtained from the next of kin. The post-mortem brain tissue of 13 patients with schizophrenia (4 males, 9 females; mean age: 52.23 ± 10.53
Qualitative observations
Previously, we had shown that in human brain regions with a developed BBB the vast majority of capillary endothelial cells express ABCB1 (Bernstein et al., 2014). This has to be taken into account, since capillaries in the brain regions selected for the current study belong to this type of capillaries (Fig. 1A–D). In the medial habenula many ABCB1-immunopositive capillaries were embedded in a network of ABCB1-immunoreactive nerve fibers (Fig. 1E–F). Qualitative inspection of the brain sections
Discussion
BBB abnormalities are increasingly recognized as a contributing factor in schizophrenia pathophysiology, with ABCB1 being an important part of disturbed BBB function (see introduction). Our immunohistochemical findings demonstrate the absence of wide-spread alterations of ABCB1 expression in brains of patients with schizophrenia. Instead, significant numerical deficits of ABCB1 immunopositive capillaries and neurons were found in the habenula only. In contrast, a Dutch group (De Klerk et al.,
Limitations of the study
A major limitation of this study is the relatively small number of cases and the lack of data on the cumulative neuroleptic exposure of some schizophrenia patients. A further limitation is given by the method used (ABCB1 immunohistochemistry on 20 μm thick sections), which does not allow to estimate capillary length densities. Another limitation may result from the gender distribution between the cohorts (control cases: 7 males, 2 females; schizophrenia group: 4 males, 9 females; p = 0.080), since
Conclusions
Schizophrenia-related decrease in capillary and neuronal ABCB1 expression in the habenular complex might have consequences for brain concentrations of proinflammatory cytokines and for purinergic neurotransmission.
Role of funding source
The study was funded by the Otto-von-Guericke-University Magdeburg (intramural grants).
Contributors
HGB did analyses and wrote manuscript; JH did analyses; HD did biostatistics; JS did analyses; BB donated human brain material and wrote the manuscript; JP planned the study, donated material, and wrote manuscript.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgment
The authors wish to thank K. Paelchen and B. Jerzykiewicz for their technical assistance.
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