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Cerebral Cortex Advance Access published online on July 16, 2008
Cerebral Cortex, doi:10.1093/cercor/bhn107
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Published by Oxford University Press 2008.

Neuregulin-1 Modulates Hippocampal Gamma Oscillations: Implications for Schizophrenia

André Fisahn1, Jörg Neddens2, Leqin Yan2 and Andrés Buonanno2

1 Department of Neuroscience, Karolinska Institute, SE-171 77 Stockholm, Sweden, 2 Section on Molecular Neurobiology, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20814, USA

Address correspondence to Andrés Buonanno, PhD, Section on Molecular Neurobiology, Building 35, Room 2C-1000, 35 Lincoln Drive, National Institutes of Health, Bethesda, MD 20892-3714, USA. Email: buonanno{at}mail.nih.gov.

Alterations in gamma-frequency oscillations are implicated in psychiatric disorders, and polymorphisms in NRG-1 and ERBB4, genes encoding Neuregulin-1 (NRG-1) and one of its receptors, designated ErbB4, are associated with schizophrenia. Here we show that NRG-1 selectively increases the power of kainate-induced, but not carbachol-induced, gamma oscillations in acute hippocampal slices. NRG-1β is more effective than NRG-1{alpha}, a splice variant with lower affinity for ErbB receptors, and neither isoform affects the network activity without prior induction of gamma oscillations. NRG-1β dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 ± 496%) and mice (710 ± 299%). These effects of NRG-1β are blocked by PD158780, a pan-specific antagonist of ErbB receptors, and are mediated specifically via ErbB4 receptors, because mice harboring a targeted mutation of ErbB4 do not respond to NRG-1. Moreover, we demonstrate that 50% of gamma-amino butyric acidergic parvalbumin (PV)–positive interneurons, which heavily contribute to the generation of gamma oscillations, express ErbB4 receptors. Importantly, both the number of PV-immunoreactive interneurons (–31%) and the power of kainate-induced gamma oscillations (–60%) are reduced in ErbB4 knockout mice. This study provides the first plausible link between NRG-1/ErbB4 signaling and rhythmic network activity that may be altered in persons with schizophrenia.

Key Words: ErbB4 • hippocampus • interneuron • mouse • parvalbumin • rat


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