Neuregulin-1 Modulates Hippocampal Gamma Oscillations: Implications for Schizophrenia

• Published in: Cerebral cortex (New York, N.Y. 1991) Vol. 19; no. 3; pp. 612 - 618
• Main Authors: Fisahn, André, Neddens, Jörg, Yan, Leqin, Buonanno, Andrés
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2009; Oxford Publishing Limited (England)
• Subjects: Animals; Biological Clocks - physiology; Electrophysiology; ErbB4; hippocampus; Hippocampus - physiology; In Vitro Techniques; interneuron; Interneurons - metabolism; Interneurons - pathology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; mouse; Neuregulin-1 - physiology; parvalbumin; Parvalbumins - metabolism; rat; Rats; Rats, Wistar; Receptor, Epidermal Growth Factor - deficiency; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-4; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - physiopathology; mouse; interneuron; hippocampus; rat; ErbB4; parvalbumin
• ISSN: 1047-3211; 1460-2199; 1460-2199
• DOI: 10.1093/cercor/bhn107

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-1α, 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.