Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors.
Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia.
Kwon
Oh Bin
OB
Section on Molecular Neurobiology, Building 35, Room 2C-1000, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-3714, USA.
Paredes
Daniel
D
Gonzalez
Carmen M
CM
Neddens
Jörg
J
Hernandez
Luis
L
Vullhorst
Detlef
D
Buonanno
Andres
A
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D020890:Neuregulin-1; D050638:Receptors, Dopamine D4; D018698:Glutamic Acid; D004298:Dopamine