DA negatively regulates IGF-I actions implicated in cognitive function via interaction of PSD95 and nNOS in minimal hepatic encephalopathy

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Abstract

Insulin-like growth factor I (IGF-I) has been positively correlated with cognitive ability. Cognitive decline in minimal hepatic encephalopathy (MHE) was shown to be induced by elevated intracranial dopamine (DA). The beneficial effect of IGF-I signaling in MHE remains unknown. In this study, we found that IGF-I content was reduced in MHE rats and that IGF-I administration mitigated cognitive decline of MHE rats. A protective effect of IGF-I on the DA-induced interaction between postsynaptic density protein 95 (PSD95) and neuronal nitric oxide synthase (nNOS) was found in neurons. Ribosomal S6 protein kinase (RSK) phosphorylated nNOS in response to IGF-I by recruiting extracellular signal-regulated kinase (ERK1/2). In turn, DA inactivated the ERK1/2/RSK pathway and stimulated the PSD95–nNOS interaction by downregulating IGF-I. Inhibition of the interaction between PSD95 and nNOS ameliorated DA-induced memory impairment. As DA induced deficits in the ERK1/2/RSK pathway and the interaction between PSD95 and nNOS in MHE brains, IGF-I administration exerted a protective effect via interruption of the interaction between PSD95 and nNOS. These results suggest that IGF-I antagonizes DA-induced cognitive loss by disrupting PSD95–nNOS interactions in MHE.

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Ding, S., Zhuge, W., Wang, X., Yang, J., Lin, Y., Wang, C., … Zhuge, Q. (2017, September 6). DA negatively regulates IGF-I actions implicated in cognitive function via interaction of PSD95 and nNOS in minimal hepatic encephalopathy. Frontiers in Cellular Neuroscience. Frontiers Media S.A. https://doi.org/10.3389/fncel.2017.00258

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