SfN 2010—Neuregulin-ErbB Network Is Scrutinized
The Society for Neuroscience hosted more than 30,000 researchers at Neuroscience 2010 in San Diego, 13-17 November 2010. Here, we are fortunate to receive a meeting update from Detlef Vullhorst, a research fellow at the National Institute on Child Health and Human Development, Bethesda, Maryland.
30 November 2010. This report summarizes the highlights of a symposium presented at the recent Society for Neuroscience annual meeting in San Diego, entitled “The Neuregulin Pathway: From Neural Function to Psychiatric Disorders.” The four speakers of this session covered a wide spectrum of research on the role of the neuregulin (NRG)/ErbB signaling network using developmental, genetic, electrophysiological, as well as behavioral approaches. The main focus of all presentations was to discuss how mouse models with mutations in either NRG1 or ErbB4 genes can be utilized to assess the involvement of these schizophrenia risk genes in various processes implicated in the pathophysiology of schizophrenia, such as interneuron migration and function, modulation of glutamatergic and dopaminergic neurotransmission, myelination, and neural network activity. In his introductory remarks, session chair Andres Buonanno from the National Institutes of Health in Bethesda emphasized that, despite the genetic implication and biological plausibility for an involvement of this pathway in schizophrenia, NRG/ErbB mutant mouse models should not be expected to reproduce the full spectrum of symptoms observed in affected individuals, but rather to provide insights into specific aspects and endophenotypes that contribute to the full array of the pathology of schizophrenia.
In the first talk of the session, Eva Anton from the University of North Carolina at Chapel Hill presented a series of developmental experiments that underscored the critical importance of NRG1/ErbB4 signaling for patterned tangential and radial movement of neuronal precursor cells from their birthplace to their final destinations. In particular, he focused on the migration of postnatal interneuron progenitor cells from the subventricular zone (SVZ) through the rostral migratory stream (RMS) to the olfactory bulb, and showed that conditional ablation of ErbB4 in interneuron precursors leads to their aberrant orientation and migration in the RMS (see SRF related news story).
Anton then went beyond ErbB4’s role in cell migration and presented experiments that examined the effects of selective removal of ErbB4 in Dlx5/6-expressing (mostly parvalbumin-positive) interneurons on the normal development on pyramidal cell connectivity. His lab has found preliminary evidence that dendritic spines on pyramidal neurons are altered in the in DLX5/6-ErbB4 mutant mice, suggesting that excitatory synapse development might be impaired in mice with altered GABAergic function. This genetic manipulation may also impact the probability of pyramidal neuronal firing. Anton concluded his talk by presenting evidence from behavioral experiments that DLX5/6-ErbB4 mutant mice exhibit reduced preference for social novelty, suggestive of deficits in social memory.
In the second talk of the session, Andres Buonanno presented work from his lab that tied the NRG/ErbB4 pathway to the modulation of glutamatergic plasticity, dopaminergic neurotransmission, and synchronized network activity in the hippocampus. He set out by explaining how NRG1, via activation of ErbB4 receptors, reverses the expression of early-phase LTP at CA1 glutamatergic synapses, and that, conversely, NRG1 heterozygous as well as ErbB4 mutant mice exhibit increased LTP, suggesting that NRG-ErbB4 signaling functions as “a break” on the strengthening of synapses and could therefore function to maintain the dynamic range of synapses (see SRF related news story). He then detailed how NRG1 acutely triggers the release of dopamine in the dorsal hippocampus, and that LTP reversal (depotentiation) by NRG1 is mediated by the activation of dopamine D4 receptors. Consistent with an indirect pathway that links NRG/ErbB4 signaling to glutamatergic plasticity in CA1 pyramidal neurons, he presented a detailed analysis of ErbB4 expression in the hippocampus and frontal cortex, showing that ErbB4 is expressed in GABAergic interneurons including parvalbumin (PV)-positive basket cells, but undetectable in principal neurons. Interestingly, the number of PV neurons is reduced in ErbB4 mutant mice, consistent with a defect in migration as suggested earlier by Anton. Buonanno proposed that the primary effects of NRG1 on GABAergic function are likely mediated by ErbB4 receptors expressed at glutamatergic synapses on GABAergic interneurons, but not by ErbB4 at GABAergic terminals, as suggested by other groups.
He then presented evidence on experiments that showed that NRG1 potently augments the power of hippocampal oscillatory network activity in the gamma frequency range (a type of synchronized network activity that is altered in individuals with schizophrenia), and that, like in LTP reversal, the effects of NRG1 appear to be mediated by D4 dopamine receptors. Buonanno concluded his talk by presenting a comparative analysis of full and PV-interneuron-specific ErbB4 mutant mice using a battery of electrophysiological and behavioral tests, and showed that selective ablation of ErbB4 in this subset of GABAergic interneurons replicated many, but not all, of the effects observed in the mutants lacking ErbB4 in all cells. Buonanno concluded by proposing an intimate functional partnership between ErbB4 and D4 receptor signaling in mediating the biological effects of NRG1, and suggested that their role in modulating excitatory/inhibitory balance can explain how they regulate the power of gamma oscillations.
Next, Markus Schwab from the Max Planck Institute of Experimental Medicine in Goettingen, Germany, utilized gene knockout and overexpressing mouse models to investigate the importance of NRG1 for central myelination, a process that has been suggested to be affected in schizophrenia individuals. Unlike in the peripheral nervous system, where NRG1 is indispensable for proliferation, migration, and differentiation of myelinating Schwann cells, conditional ablation of the gene in CNS neurons using NEX-Cre surprisingly did not result in any discernible effects on axon myelination in the corpus callosum (see SRF related news story). However, detailed behavioral analyses of NRG1 mutant mice revealed changes in a number of paradigms, such as reduced activity in the elevated T-maze and open field tests, and impairments in both contextual (hippocampal-dependent) and cued (amygdala-dependent) fear conditioning. Schwab proposed that, while NRG1 appears dispensable for CNS myelination, it is likely required for normal pyramidal neuron function. In support of this idea, he presented evidence suggesting that GABAergic inhibition of pyramidal neurons in the hippocampus of NRG1 mutant mice is increased, while LTP was decreased, consistent with decreased pyramidal neuron output and reduced ambulatory activity of mutant mice.
Schwab then introduced a second line of experiments using a transgenic NRG1 overexpression mouse model. He showed that mice with more than the normal complement of NRG1 clearly hypermyelinate their central axons, demonstrating that the pathways that link NRG1 with myelination operate in both the peripheral and central nervous systems. Interestingly, depending on the NRG1 isoform used for overexpression (releasable type I or membrane-bound type III), his lab has observed different effects on LTP in hippocampal pyramidal neurons. Schwab did acknowledge, however, that the extremely large amounts of transgenic NRG1 expressed in these transgenic mice limited the extent to which the above results could be used to extrapolate the involvement of endogenous NRG1 in synaptic functions. He concluded by mentioning that his group is currently developing new mouse lines in which expression of the transgene can be acutely regulated to allow for better spatial and temporal control of NRG1 overexpression.
In the last talk of the symposium, Lorna Role from SUNY at Stony Brook presented an electrophysiological and behavioral analysis of mice heterozygous for membrane bound NRG1 type III (Type III Nrg+/-). These mice exhibit several behavioral abnormalities that are relevant for schizophrenia, including impaired working memory as revealed by reduced performance in the T-maze task, and profound defects in sensorimotor gating as assessed using the prepulse inhibition (PPI) test. Interestingly, some of these phenotypes such as PPI can be normalized with nicotine. Role pointed out that schizophrenia and smoking are tightly linked, and that nicotine appears to be a way of self-medication to normalize gating deficits observed in patients. In analyzing possible perturbations of the underlying circuits, she focused on the functional connectivity between the ventral hippocampus (vHipp) and the nucleus accumbens (nAcc), one of its major projection areas.
Role and colleagues used in vivo multi-electrode arrays to study the temporal coordination of activity between the vHipp and the nAcc in wild-type and type III Nrg+/- mice. They found deficits in several aspects of coupling between these two areas, indicating reduced efficacy of vHipp input into the nAcc (see SRF related news story). Underscoring the importance of nicotine, possibly signaling via α7 subunit-containing nicotinic acetylcholine receptors, Role explained that the observed deficits in PPI in type III Nrg+/- mice are fully restored by nicotine. She concluded by presenting a comparative analysis of behavioral and electrophysiological phenotypes in type III Nrg+/- and nAChRa7+/- mice, which share numerous abnormalities, and showed that in some cases (e.g., PPI), the combined effects of NRG1 type III and nAChRα7 heterozygosity in the double mutant mouse exceed the severity of the single allele defects.—Detlef Vullhorst.