ErbB4 reduces synaptic GABAA currents independent of its receptor tyrosine kinase activity.
ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy. In cortical tissue, ErbB4 associates with excitatory synapses located on inhibitory interneurons. However, biochemical and histological data described herein demonstrate that the vast majority of ErbB4 is extrasynaptic and detergent-soluble. To explore the function of this receptor population, we used unbiased proteomics, in combination with electrophysiological, biochemical, and cell biological techniques, to identify a clinically relevant ErbB4-interacting protein, the GABAA receptor α1 subunit (GABAR α1). We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR α1 expression. Moreover, we characterize a Neuregulin-mediated ErbB4 signaling modality, independent of receptor tyrosine kinase activity, that couples ErbB4 to decreased postsynaptic GABAR currents on inhibitory interneurons. Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR α1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin. Our results reveal a function of ErbB4, independent of its tyrosine kinase activity, that modulates postsynaptic inhibitory control of hippocampal interneurons and may provide a novel pharmacological target in the treatment of neuropsychiatric disorders and epilepsy.
Section on Molecular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
Robert M
RM
Mitchell
Megan J
MJ
Janssen
Irina
I
Karavanova
Detlef
D
Vullhorst
Katrina
K
Furth
Anthony
A
Makusky
Sanford P
SP
Markey
Andres
A
Buonanno
D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007395:Interneurons / Q000378:metabolism*; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D020880:Neuregulins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
D020880:Neuregulins; D011963:Receptors, GABA-A; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4
PKC; hippocampus; mIPSCs; parvalbumin; schizophrenia