title: Nicotine-induced neuroplasticity counteracts the effect of schizophrenia-linked neuregulin 1 signaling on NMDAR function in the rat hippocampus.
abstract: A high rate of heavy tobacco smoking among people with schizophrenia has been suggested to reflect self-medication and amelioration of cognitive dysfunction, a core feature of schizophrenia. NMDAR hypofunction is hypothesized to be a mechanism of cognitive dysfunction, and excessive schizophrenia-linked neuregulin 1 (NRG1) signaling through its receptor ErbB4 can suppress NMDAR function by preventing Src-mediated enhancement of NMDAR responses. Here we investigated whether chronic nicotine exposure in rats by subcutaneous injection of nicotine (0.5-1 mg/kg, twice daily for 10-15 days) counteracts the suppressive effect of NRG1β on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1β, which prevents the enhancement of NMDAR responses by the Src-family-kinase-activating peptide pYEEI in naive rats, failed to block the effect of pYEEI in nicotine-exposed rats. In naive rats, NRG1β acts only on GluN2B-NMDARs by blocking their Src-mediated upregulation. Chronic nicotine exposure causes enhanced GluN2B-NMDAR responses via Src upregulation and recruits Fyn for the enhancement of GluN2A-NMDAR responses. NRG1β has no effect on both enhanced basal GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses. Src-mediated enhancement of GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses initiate long-term potentiation (LTP) of AMPAR synaptic responses in naive and nicotine-exposed CA1 pyramidal cells, respectively. These results suggest that NRG1β suppresses LTP by blocking Src-mediated enhancement of GluN2B-NMDAR responses, but has no effect on LTP in nicotine-exposed rats. These effects of chronic nicotine exposure may counteract the negative effect of increased NRG1-ErbB4 signaling on the cellular mechanisms of learning and memory in individuals with schizophrenia, and therefore may motivate heavy smoking.
authors: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA; Department of Neurophysiology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Yoshihiko
authors: Y
authors: Yamazaki
authors: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA. Electronic address: ksumikaw@uci.edu.
authors: Katumi
authors: K
authors: Sumikawa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020890:Neuregulin-1 / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012559:Schizophrenia; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D020890:Neuregulin-1; D009538:Nicotine; D016194:Receptors, N-Methyl-D-Aspartate; C117467:neuregulin beta
keywords: Fyn; GluN2A; GluN2B; Neuregulin 1; Nicotine; Src