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Neuregulin and ErbB4: Synaptic Jacks of All Trades

3 April 2011. Signaling between neuregulin-1 (NRG1) and its receptor ErbB4 clamps down on increases in synaptic strength without changing basal properties of the synapse, according to a report in Nature Medicine published online on March 27. Researchers led by Michael Salter at the University of Toronto found that, in the hippocampus and prefrontal cortex of mice, NRG1β-ErbB4 signaling interfered with enhancement of N-methyl D-aspartate (NMDA) receptor (NMDAR) activity normally mediated by Src, a tyrosine kinase.

These findings, along with another study published January 5 in the Journal of Neuroscience describing a synapse-promoting effect of NRG1 specific to interneurons, present several roles for these schizophrenia susceptibility factors (see SZGene for NRG1 and ErbB4) at the synapse—both developing and fully grown. Postmortem findings suggest increased NRG1-ErbB4 signaling in schizophrenia (see SRF related news story and SRF news story), and the new studies indicate that aberrant NRG1-ErbB4 signaling could have functional repercussions at the neural circuit level. While Salter's study identifies a specific molecular mechanism that links excessive NRG1-ErbB4 signaling to the hypothesized underactive NMDA receptors in schizophrenia (see SRF hypothesis), the earlier study from Lin Mei's lab at Medical College of Georgia in Augusta finds that NRG1-ErbB4 signaling during development promotes excitatory synaptic inputs onto GABAergic interneurons—a cellular venue of growing interest both for NRG1-ErbB4 pathways and for schizophrenia (see SRF related news story).

Blocking Src-mediated gains in synaptic strength
Though NRG1 and ErbB4 are recognized as neurodevelopmental actors, Salter's group focused on their effects in fully developed synapses in brain slices made from adult mice. Building on previous studies showing that NRG1-ErbB4 signaling blocks long-term potentiation (LTP) that relies on NMDARs in the hippocampus (e.g., Pitcher et al., 2008), first author Graham Pitcher and colleagues explored whether Src—a tyrosine kinase that phosphorylates NMDARs and boosts their function—was involved.

Recording from CA1 neurons of the hippocampus while stimulating their inputs to evoke synaptic responses, the researchers found that, when a Src-activator was introduced inside the cell, the evoked response through NMDARs gradually doubled in size over 15 minutes. When NRG1β was added to the slice prior to the Src-activator, however, this progressive increase did not appear, even after 30 minutes. This blockade required ErbB4: the Src-activated NMDAR enhancement occurred in the presence of NRG1β when an ErbB4 inhibitor was used, and in CA1 neurons from mutant mice lacking ErbB4. The NRG1β-ErbB4 blockade also prevented gains in the entire synaptic response, which comprises AMPARs as well as NMDARs, likely by interfering with NMDAR-dependent calcium entry, which in turn boosts AMPAR responses.

This NRG1β-ErbB4 blockade took place only in the context of Src activation, leaving baseline properties of the synaptic response—like amplitude, time course, and voltage-dependence of evoked NMDA currents—untouched by perturbations to NRG1β-ErbB4 signaling. The context-dependence of the blockade is not just a hippocampal phenomenon, as it held true for excitatory synapses onto pyramidal neurons of the prefrontal cortex as well.

Stimulating patterns
Not only could NRG1β-ErbB4 signaling prevent synaptic gains induced by an Src activator artificially introduced into a neuron, but it could prevent synaptic strengthening that normally results from high-frequency stimulation, called theta burst stimulation, of a neuron's synaptic inputs. Building on their previous work showing that theta burst stimulation produces LTP in CA1 cells through Src-mediated NMDAR enhancement (Lu et al., 1998), the researchers found that adding NRG1β to the brain slice prior to stimulation prevented increases in synaptic strength. This effect was specific to LTP induction—NRG1β had no effect on synaptic responses prior to or after potentiation—and it required Src, as NRG1β could not block the residual LTP left in mutant mice lacking Src.

Close inspection of the synaptic responses evoked during theta burst stimulation revealed that NRG1β compromised the ability of a neuron to integrate rapidly occurring inputs: the amplitude of the synaptic response during a high-frequency burst of input fell short of that measured in the absence of NRG1β—though NRG1β did not affect the EPSP to a single stimulus in isolation. This raises the possibility that excessive NRG1β-ErbB4 signaling may alter oscillatory activity patterns in the brain—something the authors suggest might contribute to the cognitive difficulties and psychosis of schizophrenia.

Forming fledgling synapses
NRG1 also has a hand in shaping developing synapses, a role that was explored in the second study by first author Annie Ting and colleagues in Lin Mei's lab. They found that NRG1 applied for two days to cultured neurons from embryonic rat or mouse brain increased the number and size of nascent glutamatergic synapses on interneurons, but not on glutamatergic neurons. This synaptogenic effect was reflected by more and larger clusters of post-synaptic density-95 (PSD-95) staining, a marker of excitatory synapses, and by an increase in size and frequency of spontaneously occurring miniature excitatory post-synaptic currents (mEPSCs) in interneurons.

Endogenous NRG1 likely promotes new synapse formation, the authors suggest, because interfering with its binding to ErbB4 with an exogenously applied ErbB4-like peptide reduced the number and size of PSD-95 clusters in interneurons. Similarly, brain slices from mice lacking ErbB4 specifically in parvalbumin-containing interneurons had smaller and fewer mEPSCs compared to those with ErbB4 intact. These same mice exhibit schizophrenia-related behaviors (Wen et al., 2010).

These results complement findings last year that documented how NRG1-ErbB4 signaling could promote inhibitory synapse formation onto excitatory neurons, as well as excitatory synapse formation onto interneurons (Fazzari et al., 2010; see SRF related news story). Together, the studies start to define the types of synapses influenced by NRG1-ErbB4, plucking specific parts of the brain's circuitry out of its complex wiring diagram. Likewise, Salter's study reveals that NRG1-ErbB4 signaling acts specifically on Src-mediated processes that are initiated under certain circumstances. As research identifies with increasing specificity the molecular outcomes of schizophrenia-like perturbations to NRG1-ErbB4 signaling, this will fill out our understanding of the brain in schizophrenia and provide clues for therapeutics.—Michele Solis.

Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, Salter MW. Schizophrenia susceptibility pathway neuregulin-1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med. 2011 Mar 27. Abstract

Ting AK, Chen Y, Wen L, Yin DM, Shen C, Tao Y, Liu X, Xiong WC, Mei L. Neuregulin-1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci. 2011 Jan 5;31(1):15-25. Abstract

Comments on News and Primary Papers
Primary Papers: Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons.

Comment by:  Bo Li
Submitted 7 April 2011 Posted 7 April 2011

As both NRG1 and ErbB4 have been linked to schizophrenia,...  Read more

View all comments by Bo Li

Primary Papers: Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors.

Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 20 April 2011 Posted 20 April 2011

The study by Pitcher and colleagues incorporates a series...  Read more

View all comments by Amanda Jayne Law

Comment by:  Michael CahillPeter Penzes
Submitted 29 April 2011 Posted 29 April 2011
  I recommend the Primary Papers

The recent study by Pitcher et al. provides a novel...  Read more

View all comments by Michael Cahill
View all comments by Peter Penzes
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