The control limit hypothesis of schizophrenia

Over the last half century, we have made little progress in the treatment of schizophrenia. A key contributor to this is an insufficient understanding of what is causing the disorder. There are currently two broad families of hypotheses: those focused on a dopaminergic dysfunction, and those focused on a glutamatergic dysfunction. Based on recent findings that antipsychotic drugs exhibit cell-type specific and long-term effects on cortical circuit function, we integrate the two hypotheses into what we call the control limit hypothesis of schizophrenia. It builds on the assumption that schizophrenia is the result of a developmental miswiring of cortical circuits that is based on glutamatergic dysfunction and causes aberrant cortical activity dynamics. These cortical alterations likely underlie cognitive dysfunction, one of the core treatment-resistant symptoms of schizophrenia. The control limit hypothesis further postulates that the brain responds to and can partially mitigate these aberrant cortical dynamics by increasing dopamine levels in the striatum. When this regulatory system is driven to a control limit and dopamine levels exceed a given threshold, psychosis emerges. Beyond explaining much of the existing data, the hypothesis makes several predictions about cortical function testable in mice and humans.