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Summary Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period downregulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular, and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity. [ABSTRACT FROM AUTHOR]

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling. [Display omitted] • Spinal ErbB4+ neurons are activated by heat and synapsed by TRPV1+ nociceptors • Heat sensation is reduced by ErbB4+ neuron ablation or inhibition • Augmented effect on heat sensation by inhibiting ErbB4+, SST+, and CCK+ neurons together • NRG1-ErbB4 signaling promotes heat sensation and hypersensitivity How heat signals are processed in the spinal cord remains unclear. Wang et al. found that ErbB4+ excitatory interneurons are activated by noxious heat, and they participate in heat sensation in mice. In addition, the neuregulin-ErbB4 signaling regulates heat sensation and contributes to heat hypersensitivity under pathological conditions. [ABSTRACT FROM AUTHOR]

Summary Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4 , which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4−/− mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder. [ABSTRACT FROM AUTHOR]

Neuregulins (NRGs) comprise a large family of growth factors that stimulate ERBB receptor tyrosine kinases. NRGs and their receptors, ERBBs, have been identified as susceptibility genes for diseases such as schizophrenia (SZ) and bipolar disorder. Recent studies have revealed complex Nrg/Erbb signaling networks that regulate the assembly of neural circuitry, myelination, neurotransmission, and synaptic plasticity. Evidence indicates there is an optimal level of NRG/ERBB signaling in the brain and deviation from it impairs brain functions. NRGs/ERBBs and downstream signaling pathways may provide therapeutic targets for specific neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Summary: Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Summary: Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNrg1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling. [ABSTRACT FROM AUTHOR]

In this issue of Neuron, Yin et al. (2013) demonstrate that overexpression of Neuregulin 1 causes synaptic dysfunction and schizophrenia-like behavioral deficits. These abnormalities can be reverted by restoring normal levels of Neuregulin 1, opening possibilities for the treatment of mental disease. [ABSTRACT FROM AUTHOR]

Summary Top-down attention is crucial for meaningful behaviors and impaired in various mental disorders. However, its underpinning regulatory mechanisms are poorly understood. We demonstrate that the hippocampal-prefrontal synchrony associates with levels of top-down attention. Both attention and synchrony are reduced in mutant mice of ErbB4, a receptor of neuregulin-1. We used chemical genetic and optogenetic approaches to inactivate ErbB4 kinase and ErbB4+ interneurons, respectively, both of which reduce gamma-aminobutyric acid (GABA) activity. Such inhibitions in the hippocampus impair both hippocampal-prefrontal synchrony and top-down attention, whereas those in the prefrontal cortex alter attention, but not synchrony. These observations identify a role of ErbB4-dependent GABA activity in the hippocampus in synchronizing the hippocampal-prefrontal pathway and demonstrate that acute, dynamic ErbB4 signaling is required to command top-down attention. Because both neuregulin-1 and ErbB4 are susceptibility genes of schizophrenia and major depression, our study contributes to a better understanding of these disorders. Video Abstract [ABSTRACT FROM AUTHOR]

Summary GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 ( NRG1 ) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, we tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo . ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. Our data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development. Video Abstract [ABSTRACT FROM AUTHOR]

The functional expression of Ca2+-activated K+ channels (KCa) in developing chick ciliary ganglion (CG) neurons requires interactions with target tissues and preganglionic innervation. Here, we show that the stimulatory effects of target tissues are mediated by an isoform of TGFbeta. Exposure of cultured CG neurons to TGFbeta1, but not TGFbeta2 or TGFbeta3, caused robust stimulation of KCa. The KCa stimulatory effects of target tissue extracts were blocked by a neutralizing pan-TGFbeta antiserum but not by specific TGFbeta2 or TGFbeta3 antisera. Intraocular injection of TGFbeta1 caused robust stimulation of KCa, whereas intraocular injection of pan-TGFbeta antiserum inhibited expression of KCa in CG neurons developing in vivo. The effects of TGFbeta1 were potentiated by beta-neuregulin-1, a differentiation factor expressed in preganglionic neurons.

We report here that neuregulin (NRG) isoforms with a conserved cysteine-rich domain (CRD) in their N terminus regulate expression of nicotinic acetylcholine receptors (nAChRs) at developing interneuronal synapses and report the isolation of transmembrane NRG isoforms with this CRD within the N-terminal portion. CRD-NRG mRNA and immunoreactive protein are detected early in developing presynaptic (visceral motor) neurons. The levels of expression of CRD-NRG peak prior to the formation of synapses with their postsynaptic partners, the ganglionic sympathetic neurons. Recombinant CRD-NRG mimics the effects of presynaptic input on target neurons. Functional deletion of CRD-NRG from presynaptic neurons abolishes the upregulation of nAChR expression induced by input-derived soluble material. Thus, CRD-NRG appears to be both a necessary and a sufficient signal for the control of neuronal nAChR expression during synaptogenesis.

The migration of neuronal precursors along radial glial fibers is a critical step in the formation of the nervous system. In this report, we show that neuregulin-erbB receptor signaling plays a crucial role in the migration of cerebellar granule cells along radial glial fibers. Granule cells express neuregulin (NRG), and radial glia cells express erbB4 in the developing cerebellum and in vitro. When the glial erbB receptors are blocked, neurons fail to induce radial glia formation, and their migration along radial glial fibers is impaired. Moreover, soluble NRG is as effective as neuron-glia contact in the induction of radial glia formation. These results suggest that the activation of glial erbB4 by NRG is an early critical step in the neuronal migration program.

We show that GGF/neuregulin is a mitogen for prooligodendrocytes (O4+/O1- cells), oligodendrocytes (O4+/O1+ cells), and type-2 astrocytes. Heregulin beta 1, another neuregulin isoform, is also mitogenic. The proliferative effect of glial growth factor (GGF) does not require, but is greatly potentiated by, serum factors. GGF also promotes the survival of pro-oligodendrocytes under serum-free conditions. High levels of GGF reversibly inhibit the differentiation and lineage commitment of oligodendrocyte progenitors and, in differentiated cultures, result in loss of O1 and myelin basic protein expression. All three erbB receptors are expressed by progenitors and are activated by GGF; the relative abundance of these receptors changes during differentiation. Finally, cortical neurons release a soluble mitogen for pro-oligodendrocytes that is specifically blocked by antibodies to GGF. These results implicate the neuregulins in the neuronal regulation of oligodendrocyte progenitor proliferation, survival, and differentiation.

c-RET is an orphan receptor tyrosine kinase essential for enteric neurogenesis in mice and is involved in several human genetic disorders. RET is also one of the earliest surface markers expressed by postmigratory neural crest cells in the gut. We generated anti-RET monoclonal antibodies to isolate such cells. We find that RET+ cells are antigenically and functionally distinct from neural crest stem cells (NCSCs) characterized previously. Unlike NCSCs, which are RET- and MASH1-, most RET+ cells express MASH1. Moreover, unlike NCSCs, which are multipotent and have high proliferative capacity, many RET+ cells generate only neurons following a limited number of divisions. This behavior is observed even in the presence of glial growth factor, a polypeptide that suppresses neuronal and promotes glial differentiation by NCSCs. These data provide direct evidence for the existence of committed neuronal progenitor cells and support a model of neural crest lineage diversification by progressive restriction of developmental potential.

We show that beta forms of Neu differentiation factor (NDF), homologous to acetylcholine receptor-inducing activity, glial growth factor, and heregulin, prevent apoptotic death and stimulate DNA synthesis of the E14 Schwann cell precursor, an early cell in the rat Schwann cell lineage. When precursors are exposed to NDF in defined medium, they generate Schwann cells without the requirement for DNA synthesis and with a time course that is similar to that with which Schwann cells appear in embryonic nerves in vivo. Furthermore, a neuronal signal that also mediates precursor survival and maturation is blocked by the extracellular domain of the ErbB4 NDF receptor, a protein that specifically blocks the action of NDFs. These observations provide important evidence that NDF is one of the hitherto elusive neuron-glia signaling molecules long proposed to regulate development in the Schwann cell lineage.

Structural specialization of the postsynaptic skeletal muscle membrane is in part mediated by the motor neuron-induced transcriptional regulation of synaptic muscle nuclei. ARIA, a factor that stimulates production of acetylcholine receptors (AChRs), is a candidate signaling molecule for such regulation. Here we examine the transynaptic inducing potential of this polypeptide factor. ARIA immunoreactivity is detectable at synaptic sites in vivo. In vitro, recombinant heregulin beta 1 (rHRG beta 1), the human homolog of ARIA, induces expression of the AChR epsilon gene, the subunit most sensitive to synaptic input. The inducing property of rHRG beta 1 is demonstrated most dramatically in primary muscle cultures from transgenic mice bearing an epsilon promoter-nuclear lacZ reporter transgene. Transient transfection experiments using the Sol 8 muscle cell line indicate that sequences that confer responsiveness to ARIA are located within a 150 bp epsilon subunit promoter region and are E box-independent. These results suggest that ARIA performs a vital role by directing spatially restricted gene expression at the neuromuscular junction.

Among the molecules that determine the developmental fate of sympathetic neurons from noradrenergic to cholinergic function are two apparently unrelated proteins, cholinergic differentiation factor and ciliary neurotrophic factor (CDF and CNTF, respectively). The present work suggests a structural basis for their functional overlap: sequence pattern-matching and predictive structure analysis contends that CDF and CNTF are homologous and share a common helical framework. An integrated CDF/CNTF profile also reveals similar sequence/structure motifs in a group of hematopoietic cytokines composed of granulocyte colony-stimulating factor, interleukin-6, and a novel factor called oncostatin M; a more distant relationship is indicated with interleukin-3 and interferons-alpha/beta. Evolutionary ties between neuropoietic and hematopoietic cytokines predict a distinctive tertiary architecture for the uncharacterized CDF and CNTF receptors. The intertwined cytokine/receptor networks signal a closer relationship between the molecular mechanisms underlying neuro- and hematopoiesis.

The sympathetic innervation of rat sweat glands undergoes a target-induced switch from a noradrenergic to a cholinergic and peptidergic phenotype during development. Treatment of cultured sympathetic neurons with sweat gland extracts mimics many of the changes seen in vivo. Extracts induce choline acetyltransferase activity and vasoactive intestinal peptide expression in the neurons in a dose-dependent fashion while reducing catecholaminergic properties and neuropeptide Y. The cholinergic differentiation activity appears in developing glands of postnatal day 5 rats and is maintained in adult glands. It is a heat-labile, trypsin-sensitive, acidic protein that does not bind to heparin-agarose. Immunoprecipitation experiments with an antiserum directed against an N-terminal peptide of a cholinergic differentiation factor (CDF/LIF) from heart cells suggest that the sweat gland differentiation factor is not CDF/LIF. The sweat gland activity is a likely candidate for mediating the target-directed change in sympathetic neurotransmitter function observed in vivo.