177.2 Mutations in the Neuregulin-ErbB4 Pathway Alter Dopaminergic Balance and Regulate Behaviors Relevant to Schizophrenia
Year: 2017
Type: article
Abstract: Background: Neuregulin-1 (NRG1) and ErbB4 receptor variants are associated with schizophrenia and its endophenotypes. While most studies have focused on NRG1 association with Scz, little is known about its closest homologue NRG2. Because the dopamine (DA) dysbalance and NMDA receptor hypofunction hypotheses are among the most prevalent theories for biological mechanisms underlying schizophrenia, our major goal was to investigate how alterations in NRG/ErbB4 signaling in knockout (KO) mice affect DA levels in distinct brain regions, NMDAR function and behaviors relevant to schizophrenia. Methods: NRG2 and ErbB4 expression was analyzed by in situ hybridization (RNAscope) and immunohistochemisty, using mono- and polyclonal antibodies we developed. Reverse microdialysis was used to locally deliver NRG and to concurrently measure extracellular DA and its metabolites in the dorsal striatum, medial prefrontal cortex (mPFC) and hippocampus of NRG2 and ErbB4 KO mice. Electrophysiological recordings were used to analyze plasticity and synaptic transmission. Rodent behavioral paradigms with relevance to Scz were used to analyze NRG2 and ErbB4 KOs, and to assess their response to clozapine and amphetamine (AMPH). Results: Unlike NRG1, NRG2 expression dramatically increases postnatally, and in the adult, it is extensive expressed in distinct neuronal subtypes in the cerebellum, hippocampus, neocortex, and basal ganglia. ErbB4 expression is more restricted in the neocortex and in the hippocampus its confined to GABAergic interneurons (predominantly parvalbumin positive) and mostly DAergic neurons in the mesencephalon. We identified a bidirectional NRG2/ErbB4–NMDAR signaling mechanism by which NMDAR activation acutely promotes proNRG2 processing and release, and NRG2 acutely activates ErbB4 to selectively downregulate NMDAR activity in GABAergic interneurons—a reported hallmark of the NMDAR hypofunction hypothesis. NRG2 and ErbB4 KO mice manifest a dysbalance in striatal and cortical (mPFC) extracellular DA levels, redolent to the hyper- and hypodopaminergia observed in Scz patients, respectively. Moreover, the KO mice are hyperactive, exhibit deficits in sensory-motor gating, and perform poorly on tasks requiring spatial and working memory—behavioral models relevant to schizophrenia—and performance improves transiently following acute clozapine administration. Conclusion: We have identified an intriguing functional interaction between NRG–ErbB4 signaling, NMDAR function and DA imbalances in striatal vs. extra-striatal structures that correlate with behavioral deficits relevant to schizophrenia. These findings suggest that perturbations in this or functionally similar signaling pathways could constitute a primary (upstream) pathophysiological disturbance leading to DA and NMDAR alterations associated with schizophrenia. We thank the Eunice Kennedy Shriver NICHD IRP for their generous support.
Source: Schizophrenia Bulletin
Authors: Andres Buonanno, Miguel Skirzewski
Institution: Istituto Superiore di Sanità
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2597937774