IUPHAR Review: Alpha6-containing GABA receptors - Novel targets for the treatment of schizophrenia
Journal
Pharmacological research
Journal Volume
213
Start Page
107613
ISSN
1043-6618
Date Issued
2025-03
Author(s)
Sieghart, Werner
Abstract
α6-containing GABA receptors (α6GABARs) are strongly expressed in cerebellar granule cells and are of central importance for cerebellar functions. The cerebellum not only is involved in regulation of motor activity, but also in regulation of thought, cognition, emotion, language, and social behavior. Activation of α6GABARs enhances the precision of sensory inputs, enables rapid and coordinated movement and adequate responses to the environment, and protects the brain from information overflow. The cerebellum has strong connections to multiple brain regions via closed loop circuits and is also extensively connected with the dopamine system in the prefrontal cortex, that initiates the execution of behavior. Patients suffering from schizophrenia exhibit an impaired structure and function of the cerebellum and an impaired GABAergic transmission at α6GABARs. This also impairs the function of the dopamine system, can explain a variety of schizophrenia symptoms observed, and might be one of the pathophysiological causes of schizophrenia. Enhancing GABAergic transmission at α6GABARs should thus reduce the symptoms of schizophrenia. This recently has been confirmed by demonstrating that positive allosteric modulators with high selectivity for α6GABARs can reduce positive and negative symptoms and cognitive impairment of schizophrenia in several animal models of this disorder. So far, the beneficial actions of these modulators have been demonstrated in animal models of neuropsychiatric disorders, only. Future human studies have to investigate the safety and possible side effects of these modulators and to clarify, to which extent individual symptoms of schizophrenia can be reduced by these drugs in patients during acute and chronic dosing.
Subjects
Cerebellar function in the brain
Cerebellar granule cells
Neuropsychiatric disorders
Positive modulators selective for α6-containing GABA(A) receptors
Schizophrenia
α6-containing GABA(A) receptors
SDGs
Type
review article