Abstract
Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Drug Interactions
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / physiology*
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Excitatory Postsynaptic Potentials / radiation effects
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Glutamic Acid / metabolism*
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Hippocampus / cytology
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In Vitro Techniques
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Microscopy, Confocal / methods
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N-Methylaspartate / pharmacology
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Neuregulin-1 / genetics
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Neuregulin-1 / metabolism
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Neuronal Plasticity / physiology*
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Neurons / cytology*
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Patch-Clamp Techniques / methods
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Quinazolines
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RNA Interference
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RNA, Small Interfering / pharmacology
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Rats
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Receptor, ErbB-4
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Synapses / physiology*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Synaptic Transmission / radiation effects
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Transfection / methods
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Tyrphostins / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Enzyme Inhibitors
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Neuregulin-1
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Quinazolines
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RNA, Small Interfering
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Tyrphostins
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RTKI cpd
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Glutamic Acid
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N-Methylaspartate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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ErbB Receptors
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Erbb4 protein, rat
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Receptor, ErbB-4