A negative feedback loop controls NMDA receptor function in cortical interneurons via neuregulin 2/ErbB4 signalling
| Autor: | Detlef Vullhorst, Robert M. Mitchell, Irina Karavanova, Andres Buonanno, Carolyn Keating, Swagata Roychowdhury, Jung-Hwa Tao-Cheng |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Patch-Clamp Techniques Receptor ErbB-4 Neuregulin-1 Blotting Western Fluorescent Antibody Technique Prefrontal Cortex General Physics and Astronomy AMPA receptor Hippocampus Receptors N-Methyl-D-Aspartate Mass Spectrometry Article General Biochemistry Genetics and Molecular Biology Mice Interneurons Internal medicine medicine Animals Humans Nerve Growth Factors GABAergic Neurons Neuregulin 1 Receptor Cells Cultured ERBB4 Cerebral Cortex Feedback Physiological Neurons Multidisciplinary Neuregulin Receptor biology Chemistry General Chemistry Immunohistochemistry Rats HEK293 Cells Endocrinology nervous system biology.protein NMDA receptor GABAergic Signal transduction Neuroscience Signal Transduction |
| Zdroj: | Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms8222 |
| Popis: | The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization. However, little is known about the endogenous ligands that engage ErbB4, the neural processes that activate them or their direct downstream targets. Here we demonstrate, in cultured neurons and in acute slices, that the NMDA receptor is both effector and target of neuregulin 2 (NRG2)/ErbB4 signalling in cortical interneurons. Interneurons co-express ErbB4 and NRG2, and pro-NRG2 accumulates on cell bodies atop subsurface cisternae. NMDA receptor activation rapidly triggers shedding of the signalling-competent NRG2 extracellular domain. In turn, NRG2 promotes ErbB4 association with GluN2B-containing NMDA receptors, followed by rapid internalization of surface receptors and potent downregulation of NMDA but not AMPA receptor currents. These effects occur selectively in ErbB4-positive interneurons and not in ErbB4-negative pyramidal neurons. Our findings reveal an intimate reciprocal relationship between ErbB4 and NMDA receptors with possible implications for the modulation of cortical microcircuits associated with cognitive deficits in psychiatric disorders. The neuregulin receptor ErbB4 is an important modulator of GABAergic interneurons and neural network synchronization but little is known about the endogenous ligands that engage ErbB4 and the downstream targets. Here the authors describe the existence of a cell-autonomous bidirectional pathway that links NMDA receptor activity with NRG signalling in GABAergic interneurons. |
| Databáze: | OpenAIRE |
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