Human Nicotinic Receptor Polymorphisms in Synaptic Pathology

Nearly 40% of the European Population suffers from mental disorders. These diseases are a major burden to patients and their families. Among these disorders addictions are the most important preventable causes of morbidity and mortality, smoking included as the number one. According to data from the WHO, 1.3 billion people are addicted to nicotine worldwide, causing approximately 6 million annual deaths. In spite of this knowledge most people have sever difficulties to quit smoking. The aim of this European research network is to better understand the neuropathology of substance abuse and to highlight new treatment approaches of addiction. Interestingly substance abuse seems to follow common biochemical pathways, and the same genes (mostly subunits of the nicotinic acetylcholine receptor family), which are linked to tobacco abuse, seem also to be associated with nicotine, cocaine, alcohol, opioid and cannabis misuse. In the currant project, three leading labs from Paris, Amsterdam and Vienna have united in order to study the effect of naturally occurring gene variants (so called gene polymorphisms) of different subunits of nicotinic receptors on dependence and addiction. We plan to investigate human nerve cells grown on petri dishes, but will also analyze genetically modified mice and rats. We want to compare, how these naturally occurring gene variants influence addiction and we will aim to identify new molecules, which can possibly be used to treat addiction in the future. The Vienna lab will mostly be working with human nerve cells, grown from induced pluripotent stem cells. These cells can be generated to express one or the other gene variant of nicotinic receptors. We will characterize the pharmacological and electrophysiological properties of these cells using the techniques calcium imaging and patch clamp electrophysiology and compare the effect of the different gene polymorphisms. Our research partners in Paris and Amsterdam will in parallel study genetically modified mice and rats, in order to elucidate the effect of the different polymorphisms on addiction related behavior. Finally we plan to test new molecules, which could possibly be useful to treat addiction.

Nearly 40% of the European population suffers from mental disorders. These diseases are a major burden to patients and their families. Among these disorders are (besides a lot of others) addiction and schizophrenia. Both diseases are linked to the same receptor in the brain: the nicotinic acetylcholine receptor. The aim of this European research network was to better understand the neuropathology of substance abuse as well as schizophrenia and to highlight new treatment options. In the current project, three leading labs from Paris, Amsterdam and Vienna have united in order to study the effect of naturally occurring gene variants (so called gene polymorphisms) of subunits of nicotinic receptors, such as the 7- and the dup7-subunit. The latter is especially interesting, since it only occurs in humans, but not in any other species on this planet, and can therefore not be studies easily. Our collaboration partner in Amsterdam studied nerve cells in brain slices derived from patients, who had to undergo a neurosurgical treatment. He and his team could show, that some nerve cell classes are conserved from mouse to human, but there were still significant differences between species. The labs in Paris and Vienna studied the effect of receptors containing these human specific dup7-subunit by working with human nerve cells, grown from induced pluripotent stem cells. These cells can be grown in a petri dish and by adding specific compounds they can develop into neurons, which are similar to the ones found in the human cortex. These cells can be modified to express one or the other gene variant. While in Paris these newly generated cells were transplanted into mouse brain in order to see, how they behave in this environment, we in Vienna studied the properties of those neurons still growing in petri dishes. We characterized the pharmacological and electrophysiological properties of these cells using the techniques "calcium imaging" and "patch clamp electrophysiology" and compared the effect of the different gene polymorphisms. Our findings demonstrated, that the human specific dup7-subunit is not able to form functional receptors alone. It can however co-assemble with 7, leading to receptors which are less functional. For many years, all patients have been medically treated alike. Only recently we have become aware, that people need to be separated in different groups with individual treatment schemes. In the current project we highlight the fact, that humans with different polymorphisms of the two genes which code for the 7- and the dup7-subunit will result in receptors with differing responses and might therefore react differently to pharmacological treatment(s). This project will hopefully renew the interest by pharmaceutical companies in developing medication targeting specifically the genetic alterations in patients, in an approach referred to as "precision medicine".