The Anti-social Brain in Schizophrenia: A Role of CaMKII?

Abstract

Current pharmacological therapy has limited effects on the cognitive impairments and negative symptoms associated with schizophrenia. Therefore, understanding the molecular underpinnings of this disorder is essential for the development of effective treatments. It appears that a reduction in calcium/calmodulin-dependent protein kinase II (α-CaMKII) activity is a common mechanism underlying the abnormal social behavior and cognitive deficits associated with schizophrenia. In addition, in a previous study social interaction with a partner of the same sex and weight increased the activity of α-CaMKII in rats. Here, we propose that boosting of CaMKII signaling, in a manner that counteracts this neuropsychiatric disease without disrupting the normal brain function, might ameliorate the abnormalities in social cognition and the negative symptoms of schizophrenia.

Keywords: CaMKII; biomarker; negative symptoms; schizophrenia; social interaction.

FIGURE 1

Reduced α-CaMKII induces on the cellular level an abnormal signal transduction reflected in different brain regions. In the hippocampus: a dysregulated adult neurogenesis leading to an immature dentate gyrus in the hippocampus. In the pre-frontal cortex (PFc): a malfunction of NMDA receptor signaling in the associated with dopaminergic hypo-function. In the striatum: dopamine (DA) D2 receptors in a state with a high affinity for DA leading to a hyperdopaminergic state. These mechanisms might underlie behavioral abnormalities such as the social interaction impairments and cognitive deficits seen in schizophrenia.

FIGURE 2

Boosting CaMKII signaling could improve both social and cognitive deficits in schizophrenia. Animal models of schizophrenia share the same behavioral profile, in particular social withdrawal. Impaired social interaction is associated with reduced α-CaMKII activity. If CaMKII activity was potentiated via the administration of cognitive enhancers such as (ST101), CaMKII activity in the pre-frontal cortex (PFc) and the hippocampus is increased and the social impairment is rescued. In parallel, social interaction reward increases α-CaMKII activity in the nucleus accumbens (NAc).