Neuregulin links dopaminergic and glutamatergic neurotransmission to control hippocampal synaptic plasticity

Abstract

Neuregulin-1 (NRG-1) and its receptor ErbB4 are genetically linked with schizophrenia, a complex developmental disorder of high heritability but unknown etiology that has been proposed to result from deficits in functional connectivity and synaptic plasticity. Based on pharmacological evidence, disbalances in dopaminergic and glutamatergic transmission systems are believed to contribute to its pathophysiology, but genetic data supporting a causative role for either are sparse. Stimulation of NRG-1/ErbB4 signaling inhibits or reverts hippocampal long-term potentiation at glutamatergic synapses between Schaeffer collateral afferents and CA1 pyramidal neurons (SC->CA1). We have recently demonstrated that NRG-1 regulates glutamatergic plasticity by rapidly increasing extracellular hippocampal dopamine levels and activation of D4 dopamine receptors (D4R). These new findings position NRG-1/ErbB4 signaling pathway at the crossroads between dopaminergic and glutamatergic neurotransmission and offer novel ways to consolidate genetic, functional and pharmacological data toward a better understanding of the etiological processes underlying schizophrenia, and the role of NRG-1 for normal synaptic function and plasticity. The currently available data suggest that hippocampal interneurons might play a crucial role in mediating NRG-1 induced depotentiation. This interpretation is in line with other evidence pointing towards an involvement of GABAergic cells in the etiology of schizophrenia.

Acknowledgements

The authors would like to acknowledge the Eunice Kennedy Shriver National Institute of Child Health and Human Development for their financial support.

Figures and Tables

Figure 1 Blockade of endogenous NRG/ErbB signaling reduces dopamine release in the dorsal hippocampus of live behaving rats. Catechol-O-methyl transferase (COMT) activity was blocked with 100 nM Ro-41-0960 to prevent dopamine degradation and to analyze the effects of ErbB receptor inhibition (10 µM PD158780) on dopamine release. Dopamine levels rise steadily over 25 min following the onset of Ro-41-0960 infusion, consistent with the predominant role of enzymatic degradation in the clearance of extracellular dopamine in the hippocampus.7 However, after additional infusion of the ErbB receptor inhibitor (solid squares), dopamine levels decrease significantly compared to controls that did not receive the blocker (open squares). Therefore, ErbB receptor activation is involved in the regulation of endogenous dopamine release. *p < 0.05 (2-way ANOVA). Data represent the mean ± SEM (n = 5 for both groups).