Neuregulin-1 (NRG1), a regulator of neural development, has been shown to regulate neurotransmission at excitatory synapses. Although ErbB4, a key NRG1 receptor, is expressed in glutamic acid decarboxylase (GAD)-positive neurons, little is known about its role in GABAergic transmission. We show that ErbB4 is localized at GABAergic terminals of the prefrontal cortex. Our data indicate a role of NRG1, both endogenous and exogenous, in regulation of GABAergic transmission. This effect was blocked by inhibition or mutation of ErbB4, suggesting the involvement of ErbB4. Together, these results indicate that NRG1 regulates GABAergic transmission via presynaptic ErbB4 receptors, identifying a novel function of NRG1. Because both NRG1 and ErbB4 have emerged as susceptibility genes of schizophrenia, these observations may suggest a mechanism for abnormal GABAergic neurotransmission in this disorder.

Neuregulin 1 (NRG1) is a trophic factor thought to play a role in neural development. Recent studies suggest that it may regulate neurotransmission, mechanisms of which remain elusive. Here we show that NRG1, via stimulating GABA release from interneurons, inhibits pyramidal neurons in the prefrontal cortex (PFC). Ablation of the NRG1 receptor ErbB4 in parvalbumin (PV)-positive interneurons prevented NRG1 from stimulating GABA release and from inhibiting pyramidal neurons. PV-ErbB4 −/− mice exhibited schizophrenia-relevant phenotypes similar to those observed in NRG1 or ErbB4 null mutant mice, including hyperactivity, impaired working memory, and deficit in prepulse inhibition (PPI) that was ameliorated by diazepam, a GABA enhancer. These results indicate that NRG1 regulates the activity of pyramidal neurons by promoting GABA release from PV-positive interneurons, identifying a critical function of NRG1 in balancing brain activity. Because both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study provides insight into potential pathogenic mechanisms of schizophrenia and suggests that PV-ErbB4 −/− mice may serve as a model in the study of this and relevant brain disorders.is a family of trophic factors with an epidermal growth factor (EGF)-like domain (1, 2). It acts by stimulating the ErbB family of receptor tyrosine kinases ErbB2, -3, and -4. NRG1 binds only to ErbB3 or ErbB4, but not to ErbB2. On the other hand, ErbB2 and ErbB4 are most active in response to NRG1 stimulation whereas the kinase activity of ErbB3 is impaired. Thus, ErbB2 and ErbB3 function by forming heterodimers with each other or with ErbB4, but an ErbB4 homodimer is functional by itself (2). NRG1 has been implicated in many aspects of neural development including neuron migration, axon projection, myelination, synapse formation, and up-regulation of neurotransmitter receptor expression (2). Recently, CNS-specific mutation of ErbB2 and ErbB4 seemed to have no effect on layered structures of the cerebral cortex, hippocampus, and cerebellum or expression of NMDA receptor subtypes (3, 4), challenging existing views of NRG1 function.Both NRG1 and its receptors are distributed throughout brain regions critical for higher function in adult animals (5-8), suggesting a role of NRG1 in the brain after neural development is complete. In support of this hypothesis were observations that ErbB4 is present at the postsynaptic density of excitatory synapses presumably via interaction with PSD-95 (9-11). Moreover, ErbB4 mRNA is enriched in regions where interneurons are clustered (5) and GAD-positive neurons of the hippocampus express high levels of ErbB4 (10), suggesting that ErbB4 is enriched in GABAergic neurons. Immunohistochemical analysis indicates that ErbB4 is expressed in most if not all parvalbumin (PV)-positive interneurons in addition to glutamatergic neurons (10, 12). Intriguingly, exogenous NRG1 suppresses the induction of LTP at Schaffer collateral-CA1 synapses in the hippocampus (10, 11, 13) or reverses it (14, 15). These observ...

Synapse formation requires proper interaction between pre- and postsynaptic cells. In anterograde signaling, neurons release factors to guide postsynaptic differentiation. However, less is known about how postsynaptic targets retrogradely regulate presynaptic differentiation or function. We found that muscle-specific conditional knockout of beta-catenin (Ctnnb1, also known as beta-cat) in mice caused both morphologic and functional defects in motoneuron terminals of neuromuscular junctions (NMJs). In the absence of muscle beta-catenin, acetylcholine receptor clusters were increased in size and distributed throughout a wider region. Primary nerve branches were mislocated, whereas secondary or intramuscular nerve branches were elongated and reduced in number. Both spontaneous and evoked neurotransmitter release was reduced at the mutant NMJs. Furthermore, short-term plasticity and calcium sensitivity of neurotransmitter release were compromised in beta-catenin-deficient muscle. In contrast, the NMJ was normal in morphology and function in motoneuron-specific beta-catenin-deficient mice. Taken together, these observations indicate a role for muscle beta-catenin in presynaptic differentiation and function, identifying a previously unknown retrograde signaling in the synapse formation and synaptic plasticity.