What is the problem/issue being addressed?
The communication between neurons of the vertebrate’s brain is inhibited by an ion channel known as the GABA-A receptor. GABA-A receptors are formed by five proteins, or subunits, and their different classes are classified according to α subunit (α1–6). The differential expression of GABA-A receptors has been associated with schizophrenia or affective disorders between other pathologies or human conditions. In addition to the brain, GABA-A receptors have been detected in the peripheral nervous system of other organs such as the stomach, lungs, bladder, kidneys, liver and heart.
Schizophrenia is a severe psychiatric disorder that has a profound effect on both the individuals affected and society. Postmortem investigations of GABA-A receptor α subunit expression have found reductions in α1 and increases in α2 expression, but inconsistent results for the α5 subunit. However, the density of GABA-A receptors in schizophrenia does not appear abnormal when it is studied in living patients though positron emission tomography (PET) in contrast to what the postmortem studies have demonstrated. Some researchers and GABARPET researchers believe that these negative findings can be explained because of the lack of PET tracers with high affinity and specificity.
The immuno-positron emission tomography (immunoPET) is a non-invasive imaging technology based on tracking and quantification of radiolabeled monoclonal antibodies, antibody fragments, and peptides in vivo. Antibody imaging provides a specific and sensitive, noninvasive means for molecular detection of the cell surface proteins in vivo (e.g. ion channels), which aid diagnosis, prognosis, therapy selection, and monitoring of treatment for many diseases. Nevertheless, its success in neuroimaging is limited because intact antibodies cannot penetrate the Brain Blood Barrier (BBB) in healthy conditions. In 2019, a new type of bispecific antibody fragment, with one arm binding the neural target of interest and the other arm directed against the transferrin receptor expressed on the endothelial cells of BBB, was successfully created. This antibody fragment was able to cross the BBB, and it was used to visualize in vivo intrabrain amyloid-beta.
Why is it important for society?
Schizophrenia affects approximately 24 million people or 1 in 300 people (0.32%) worldwide. It is frequently associated with significant distress and impairment in personal, family, social, educational, occupational, and other important areas of life. The diagnosis of schizophrenia is clinical, made exclusively after obtaining a full psychiatric history and excluding other causes of psychosis. However, as other psychiatric disorders, schizophrenia no specific marker has been established thus far, and the development of antibody-based PET probes could help find them. Therefore, the high specificity of antibodies could be used to detect each of the 19 subunits of GABA-A receptors. In this way, new immunoPET tools could be developed to look for new biomarkers in neuropsychiatric disorders. In addition, this approach could be applied to other ion channels in the nervous system.
In this research project, GABARPET researchers will utilize a completely novel approach to study the GABA-A receptor in the nervous system, which is expected to yield unprecedented insights into various diseases (e.g. Alzheimer's disease, epilepsy, schizophrenia, anxiety, etc.) and human conditions (Down syndrome, autism, etc..) in the future.
What are the overall objectives?
The goal of GABARPET researchers is to develop novel immunoPET radioligands capable of non-invasively detecting changes in GABA-A receptor subunits linked to neuropsychiatric disorders.
