Hanns Möhler`s research interest is focused on the therapeutic neuroscience of brain disorders with a special emphasis on anxiety disorders, memory deficits, schizophrenia and epilepsy. In this endeavor he successfully uses drugs as tools, in particular benzodiazepines, to identify molecular control elements of emotion and cognitive behavior. A new pharmacology arose from his work, which permits the rational design of novel hypnotics, non-sedative anxiolytics, memory enhancers, antipsychotics and antiepileptics. These achivements also reflect the excellence of his collaborators, in particular Uwe Rudolph, Jean-Marc Fritschy, Dietmar Benke, Florence Crestani, Detlev Boison and Bernhard Lüscher, most of whom now hold their own professorships.
Mechanism of action of benzodiazepines
Hanns Möhler's discovery of the benzodiazepine receptor in 1977 (ref. 15) became a citation classic and - by its link to GABAA receptors (ref. 17) - provided the molecular basis for the clarification of the mechanism of action of the benzodiazepines. More than twenty years after their introduction into medicine, benzodiazepines began to be recognized as positive allosteric modulators of GABAA receptors. He also discovered Flumazenil (Anexate), the first benzodiazepine antagonist introduced into medicine (ref. 16). The elucidation of the protein structure of the GABAA receptors, carried out to a large extent by Hanns Möhler's group, revealed an extensive molecular heterogeneity (ref. 18). By identifying the functional and pharmacological potential of the diverse receptor subtypes, Hanns Möhler greatly advanced the therapeutic perspectives for multiple brain disorders (ref. 1,3,5,8).
New treatments for anxiety disorders were realised by identifying selective targets for anxiolytic drugs (α2GABAA receptors) which lacked sedative effects and promised to exert no or low dependence liability (ref. 13). He also opened up new perspectives on anxiety disorders.They arise at the interface of genes and the environment. Through a genetically-induced partial and regional reduction of GABAA receptors in the brain, a mouse model of anxiety was generated. A high susceptibility to threat cues was combined with otherwise normal behavior, a phenotype typical for patients afflicted with anxiety disorders (ref. 14). This model points to a developmental genetic susceptibility as a major contributing factor for anxiety disorders (ref. 2).
Specific circuits for sleep-inducing agents were found to be characterized by the expression of α1GABAA receptors (ref. 13). In this context, thalamic relay cells are particularly relevant since they limit the access of sensory information to the cerebral cortex at the onset of sleep. These cells (and also many GABAergic neurons) contain α1GABAA receptors.
Selective hippocampal GABAA receptors (α5GABAA receptors) were found to regulate spatial and temporal memory performance (ref. 9). Thus, new therapeutic approaches to memory disorders are possible based on the development of α5-selective negative allosteric modulators. Indeed, this concept has been verified pharmacologically by other groups.
Hanns Möhler focused on the two major hypotheses of schizophrenia, the GABAergic hypofunction and the glutamatergic hypofunction. To progress from concepts to drugs, α3 GABAA receptor was found to inhibit the dopaminergic system (ref. 6). On the other hand, inhibition of neuronal glycine uptake in forebrain neurons enhanced NMDA receptor function and improved psychotic symptoms as well as memory performance (ref. 4). Thus, α3 GABAA receptor agonists and glycine transporter1 inhibitors qualify as innovative therapeutics.
To overcome the present therapeutic barrier in drug resistant epilepsies, adenosine was identified as an anticonvulsant, effective in a model of refractory epilepsy. Following transplantation of genetically modified adenosine-releasing fibroblasts or neural precursor cells, effective seizure suppression was achieved in vivo, pointing to local adenosine release as a therapeutic option (ref. 11).
With the main initiative and contribution coming from Hanns-Ulrich Zeilhofer, selective GABAA receptors on spinal primary afferents and possible higher pain centers (mainly α2 GABAA receptors) were found to be prime targets for the suppression of pathological pain arising from inflammatory and neurogenic injury. These results link a selective GABAsystem to pain control. Positive allosteric modulators of α2GABAA receptors qualify as innovative, efficacous and non-sedative pain therapeutics (submitted).