Neuregulins and neuronal plasticity: possible relevance in schizophrenia.
Polymorphisms in the Neuregulin 1 (NRG1) and ErbB4 receptor genes have been associated with schizophrenia in numerous cohort and family studies, and biochemical measurements from postmortem prefrontal cortex homogenates suggest that NRG/ErbB signalling is altered in schizophrenia. Moreover, recent work from our group, and from others, indicates that NRG/ErbB signalling has a role in regulating glutamatergic transmission--an intriguing finding given that glutamatergic hypofunction has been proposed to be involved in the pathogenesis underlying schizophrenia. Here we will provide a brief background of the complexity of the NRG/ErbB signalling system. We will then focus on how NRG1 reverses (depotentiates) long-term potentiation (LTP) at hippocampal Schaeffer collateral--CA1 glutamatergic synapses in the adult brain. Specifically, we found that NRG1 depotentiates LTP in an activity- and time-dependent manner. A role of endogenous NRG for regulating plasticity at hippocampal synapses is supported by experiments demonstrating that ErbB receptor antagonists completely block LTP depotentiation by brief theta-pulse stimuli, a subthreshold stimulus paradigm that reverses LTP in live animals. Preliminary results indicate that NRG1-mediated LTP depotentiation is NMDA receptor independent, and manifests as an internalization of GluR1-containing AMPA receptors. The importance of the NRG/ ErbB signalling pathway in regulating homeostasis at glutamatergic synapses, and its possible implications for schizophrenia, will be discussed.
Buonanno
Andrés
A
Section on Molecular Neurobiology, National Institute of Child Health and Human Development, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Kwon
Oh-Bin
OB
Yan
Leqin
L
Gonzalez
Carmen
C
Longart
Marines
M
Hoffman
Dax
D
Vullhorst
Detlef
D
D001921:Brain / Q000503:physiopathology*; D014644:Genetic Variation; D006801:Humans; D017774:Long-Term Potentiation; D020890:Neuregulin-1 / Q000502:physiology; D020880:Neuregulins / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology*; D015398:Signal Transduction
D020890:Neuregulin-1; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases