Role of alpha-6 GABA-A Receptors in Neuropsychiatric Diseases

GABAA receptors (gamma-amino butyric acid type A receptors) are the site of action of many clinically important drugs, such as benzodiazepines or barbiturates and the targets for sleep medications, anxiolytics, or diverse narcotics. They are the major inhibitory transmitter receptors in the brain. These GABA-gated chloride channels are composed of five subunits that can belong to different subunit classes. Multiple GABAA receptor subtypes with different localization and function thus exist. Drugs either modulate GABA-evoked chloride influx or directly induce channel opening via different allosteric binding sites. In the course of a completed FWF project, we identified and characterized a new binding site at the interface between two subunits of GABAA receptors. In addition, we reported the first functionally selective modulators for alpha6 - containing receptor subtypes which are present almost exclusively in the cerebellum. This compound raised the interest of our partner, Prof. Lih-Chu Chiou from the National Taiwan University. She studies neuropsychiatric diseases with sensorimotor gating deficit, such as schizophrenia, Tourette syndrome, attention deficit hyperactivity and obsessive compulsive disorders. She collected convincing evidence for a critical role of these alpha6 -containing GABAA receptors in the cerebellum of animals with sensorimotor gating deficit like symptoms that mimic certain aspects of the above mentioned diseases. Our partners lab investigations were initiated by a human case-report on a patient suffering from intractable motor tics that were alleviated by the leave extract of a local herb, glorybower. The Chiou lab demonstrated that the plant ingredient KLP-1 acts on cerebellar alpha6 -containing GABAA receptors, and positively influences sensorimotor gating in the animal models. In the initiation phase of our collaboration LC Chiou already tested our selective compound 6, and found it also to be active in one of her animal models. We will therefore combine our experimental techniques and jointly investigate the specific GABAA receptors and the binding sites by which our compound 6 and by her plant- constituent KLP-1 can restore the sensorimotor gating deficit. At the Center for Brain Research (Medical University of Vienna) we will identify in vitro the precise receptor subtypes on which KLP-1 and compound 6 act, and the binding sites mediating their action. The lab of our Taiwanese partner will compare the effects of both these compounds in healthy animals and in animal models that mimic sensorimotor gating deficit. Both of us together, and in a team with our respective local collaborators, aim to generate and investigate novel compounds exhibiting higher potency and selectivity for these binding sites for a possible future therapeutic application.

Progress in the development of molecules, which act in the cerebellum at so-called alpha6- containing GABA-A receptors: We are on the finishing line (in 2020) in one of many projects which aim to improve medicines that act in the brain. To understand our complex brain well enough to remedy aberrant function is a challenge taken up by many labs around the world. While therapies that do not rest on medication are slowly on the rise, many situations still require medication as an essential element in therapy. In this project the focus is on a phenomenon called "sensorimotor gating deficit". This is an unconscious process which enables us to adapt to stimuli and helps the brain to suppress responding to each incoming stimulus. Put simply, it is easier to ignore a stimulus after a similar one has occurred. This ability for unconscious adaptive inhibition has been shown to be compromised in several neuropsychiatric constellations (e.g. in Tourette syndrome or in schizophrenia). Our Taiwanese project partners discovered that the cerebellum is likely involved in this unconscious process. At the level of the cells and molecules which comprise the cerebellum, we focused on a family of inhibitory receptor molecules known as GABA-A receptors. These are further organized into many subtypes, among which are some that are characteristically found in the cerebellum and contain so-called alpha6 subunits. During the course of the project we identified and improved "alpha6- selective" molecules that were synthesized by our colleagues at Vienna Technical University and a lab in the U.S. We performed a very thorough "in vitro" testing of the molecules, representing an essential milestone in the long path of a molecule from the first description to a possible use as human medication. Until testing in humans would be possible, many more milestones have to be reached - our project partners, the Chiou lab (Taiwan) and the Savic lab (Belgrade; Serbia) demonstrated that some of our molecules can in fact improve compromised sensorimotor gating, and additional effects of models of migraine and trigeminal neuropathic pain have also been observed. It was thus demonstrated that (reduced) sensorimotor gating can actually be restored by targeted influence on cerebellar signal transduction - a finding which hopefully will also hold in humans. Beyond the cerebellum, our substances also show activity in the trigeminal signal pathway, thus a novel promise in the treatment of migraine and trigeminal neuropathy. More basic research is still needed, as only a part of the long road to a medication has been travelled. Most notably, this research contributes to a completely novel, first in kind mechanism of action towards improving syndromes which are notoriously difficult to treat.