Cellular effectors and transduction pathways as therapeutic targets in cholinergic-dependent neuropsychiatric disorders

The impairment of working memory and the subsequent decrease in cognitive function is a prominent feature of widespread neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia and also characterizes the decrease in cognitive function that occurs during natural aging. The working memory process may partially depend on acetylcholine-evoked depolarization of prefrontal cortex layer V pyramidal neurons. Working memory and cognitive functions are improved by the activation of M1 cholinergic muscarinic receptors in prefrontal cortex neurons. The activation of muscarinic receptors to improve working memory is impractical due to serious side effects. We discuss our recent findings that acetylcholine evokes depolarization in prefrontal cortex pyramidal neurons due to M1 muscarinic receptor-mediated activation of the G protein βγ subunit-dependent transduction system and Nav1.9-type Na + channels. Our results indicate that the depolarization of pyramidal neurons can be reinforced and working memory presumably strengthened not only by the activation of M1 muscarinic receptors but also by the activation of the transduction system linked to βγ subunits and/or the activation of Nav1.9 channels.