Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex.
Recent linkage studies have identified a significant association of the neuregulin gene with schizophrenia, but how neuregulin is involved in schizophrenia is primarily unknown. Aberrant NMDA receptor functions have been implicated in the pathophysiology of schizophrenia. Therefore, we hypothesize that neuregulin, which is present in glutamatergic synaptic vesicles, may affect NMDA receptor functions via actions on its ErbB receptors enriched in postsynaptic densities, hence participating in emotional regulation and cognitive processes that are impaired in schizophrenia. To test this, we examined the regulation of NMDA receptor currents by neuregulin signaling pathways in prefrontal cortex (PFC), a prominent area affected in schizophrenia. We found that bath perfusion of neuregulin significantly reduced whole-cell NMDA receptor currents in acutely isolated and cultured PFC pyramidal neurons and decreased NMDA receptor-mediated EPSCs in PFC slices. The effect of neuregulin was mainly blocked by application of the ErbB receptor tyrosine kinase inhibitor, phospholipase C (PLC) inhibitor, IP3 receptor (IP3R) antagonist, or Ca2+ chelators. The neuregulin regulation of NMDA receptor currents was also markedly attenuated in cultured neurons transfected with mutant forms of Ras or a dominant-negative form of MEK1 (mitogen-activated protein kinase kinase 1). Moreover, the neuregulin effect was prevented by agents that stabilize or disrupt actin polymerization but not by agents that interfere with microtubule assembly. Furthermore, neuregulin treatment increased the abundance of internalized NMDA receptors in cultured PFC neurons, which was also sensitive to agents affecting actin cytoskeleton. Together, our study suggests that both PLC/IP3R/Ca2+ and Ras/MEK/ERK (extracellular signal-regulated kinase) signaling pathways are involved in the neuregulin-induced reduction of NMDA receptor currents, which is likely through enhancing NR1 internalization via an actin-dependent mechanism.
Gu
Zhenglin
Z
Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, USA.
Jiang
Qian
Q
Fu
Amy K Y
AK
Ip
Nancy Y
NY
Yan
Zhen
Z
D000818:Animals; D000831:Animals, Newborn; D001896:Boron Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
C107875:6-(methylamino)pyrido(3,4-d)pyrimidine; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D020890:Neuregulin-1; D019384:Nucleic Acid Synthesis Inhibitors; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; D053778:Thiazolidines; D015638:Cytochalasin D; D004533:Egtazic Acid; D016202:N-Methylaspartate; C109986:2-aminoethoxydiphenyl borate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C037068:latrunculin B