Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia.
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-1beta is more effective than NRG-1alpha, a splice variant with lower affinity for ErbB receptors, and neither isoform affects the network activity without prior induction of gamma oscillations. NRG-1beta dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 +/- 496%) and mice (710 +/- 299%). These effects of NRG-1beta 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.
Fisahn
André
A
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Neddens
Jörg
J
Yan
Leqin
L
Buonanno
Andrés
A
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D004594:Electrophysiology; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*
D020890:Neuregulin-1; D010320:Parvalbumins; C117467:neuregulin beta; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4