Poster: Neuregulin-1 application reduces PCP-induced hyperlocomotion and GABA release – potential implications for schizophrenia treatment

Poster at the annual meeting of the European Brain and Behaviour Society (EBBS) 2013, Munich (Germany)

Martin Engel, Xu-Feng Huang, Elisabeth Frank

Background: Neuregulin-1 is critical for neurodevelopment, but also found to alter acute brain signalling in adulthood. Alterations of the Neuregulin-1-ErbB4 signalling pathway are shown to be relevant for the schizophrenia pathology. ErbB4 receptors were found primarily located on GABAergic interneurons in schizophrenia-relevant brain areas, including the hippocampus. Using application of phencyclidine (PCP) both schizophrenia-like symptoms can be induced as well as GABAergic neurotransmission altered. Antagonism of PCP-induced effects was previously used as an indicator for the antipsychotic potential of a compound.

In the presented studies, we therefore explored the potential of Neuregulin-1 application to suppress PCP-induced hyperlocomotion as well as PCP-induced GABA release in the hippocampus.

Methods: For behavioural assessment, saline or PCP (3mg/kg, ip) were administered to C57Bl/6 mice (n=8 per group) with or without simultaneous icv or ip application of human recombinant Neuregulin-1 (NRG1β1-EGF-Domain). Following the injections, locomotor activity was measured for 30min in the open field. For neurotransmitter analysis, microdialysis was used to collect cerebral spinal fluid samples from the hippocampus (dCA1) of freely moving C57BL/6 mice (n=9) after a retrodialysis infusion of either PCP (1µg/kg), Neuregulin-1 (30ng/kg) or both. Samples were analysed for GABA using gas chromatograph-mass spectrometer (GC-MS).

Results: PCP application induced significant hyperlocomotion as frequently shown before. PCP-induced hyperlocomotion was, however, reduced by both icv and ip Neuregulin-1 application in a dose dependant manner. In the hippocampus, PCP application induced a significant increase of GABA levels 10min after infusion. Neuregulin-1 showed a tendency to increase GABA release. When co-administered, however, Neuregulin-1 suppressed PCP-induced GABA release altogether, remaining at baseline levels.

Conclusion: With Neuregulin-1 application being in a phase II trial for heart disease, these results suggest that Neuregulin-1 might also be a potential treatment option for schizophrenia. In current experiments we are using primary cell cultures to further explore the antipsychotic potential of Neuregulin-1.

Download the Poster: Engel et al 2013 EBBS Poster

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