Abstract
SummaryThe Ca2+/Calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity and has been implicated in various neurological conditions, including schizophrenia. Here, we characterize six different CaMKIIα variants found in patients with schizophrenia. Only R396stop disrupted the 12-meric holoenzyme structure, GluN2B binding, and synaptic localization. Additionally, R396stop impaired T286 autophosphorylation that generates Ca2+-independent “autonomous” kinase activity. This impairment in T286 autophosphorylation was shared by the R8H mutation, the only mutation that additionally reduced stimulated kinase activity. None of the mutations affected the levels of CaMKII expression in HEK293 cells. Thus, impaired CaMKII function was detected only for R396stop and R8H. However, two of the other mutations have been later identified also in the general population, and not all mutations found in patients with schizophrenia would be expected to cause disease. Nonetheless, for the R396stop mutation, the severity of the biochemical effects found here would predict a neurological phenotype.
Highlights
Schizophrenia is a chronic, debilitating, neuropsychiatric disorder that affects an individual’s ability to interpret reality and function normally
We characterize six different CaMKIIa variants found in patients with schizophrenia
R396stop impaired T286 autophosphorylation that generates Ca2+-independent ‘‘autonomous’’ kinase activity. This impairment in T286 autophosphorylation was shared by the R8H mutation, the only mutation that reduced stimulated kinase activity
Summary
Schizophrenia is a chronic, debilitating, neuropsychiatric disorder that affects an individual’s ability to interpret reality and function normally. There is a major unmet need for antipsychotics that improve symptoms like cognitive dysfunction Cognitive function such as learning and memory are thought to require long-term potentiation (LTP) of hippocampal synapses, which in turn requires the Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKIIa+/À mice have been described to have a schizophrenia-related phenotype, including aggressive behavior, immature dentate gyrus (DG), and impaired working memory (Yamasaki et al, 2008). Though this discovery was made over a decade ago, little progress has been made in understanding the potential role of CaMKII dysregulation in schizophrenia pathophysiology
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