Prefrontal and Striatal Catecholamine Dysfunction in the Neuronal Rictor Null

Abstract

Disruption in insulin signaling is a mechanism hypothesized to underlie many neurologic and psychiatric disorders. Insulin signaling is accomplished by a complex array of intracellular effectors, including the protein kinase Akt. Akt, in turn, is a protein kinase regulated by growth factor, neurocrine, and hormonal factors, which is independently linked to psychiatric and neurologic disease, particularly schizophrenia. Recent data from our lab indicate it is also a common mechanism implicated in control of both the DAT and NET function in brain. The activity of Akt is driven by phosphorylation of this protein at two key residues: Ser473 by mTOR/RICTOR (mammalian target of rapamycin complex 2) and Thr308 by PDK1 (phosphoinositide-dependant kinase 1). Utilizing Cre-loxP technology to delete RICTOR gene in Nestin-expressing cell population, we created a transgenic mouse with disrupted neuronal Akt activity, due to severe impairment in Ser-473 phosphorylation of Akt. At a behavior level, the neuronal Rictor knockout (nKO) mouse exhibits many phenotypes that characterize animal models of schizophrenia, including PPI (pre-pulse inhibition) deficits, open field hyperlocomotion, and hypersensitivity to the psychomotor activating effects of amphetamine. These behavioral phenotypes were previously explained by dysfunctions of the dopaminergic system. However, emerging evidence suggests participation of both DA and NE circuits. At a neurochemical level, our data signifies disturbances in total monoamine homeostasis, with significant decreases in tissue DA content and elevations in NE tissue content, in both prefrontal cortex and dorsal striatum. Intriguingly, marked upregulation of the NET in cortical regions is a potential mechanism underlying the neurochemical and behavioral disruptions in the Rictor-nKO, as the Rictor-nKO demonstrates increased NET expression, and inhibition of the NET restores PPI and cortical DA deficits toward wild type levels. Here, we use the RICTOR KO mouse to analyze how the newly discovered molecular phenotype of disturbed interconnectivity between dopaminergic and noradrenergic systems may produce well-known behavioral phenotypes modeling psychiatric disorders, including schizophrenia, ADHD, major depression, and drug addiction.