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Interneurons Are Stage for Neuregulin 1, ErbB4 Interplay

14 April 2010. A study published online in Nature today, in combination with a paper from earlier this year in PNAS, points to parvalbumin-containing interneurons as a key venue for neuregulin-1 (NRG1) and ErbB4 signaling in the cerebral cortex. These papers put attention squarely on the brain's inhibitory circuits when considering the function of NRG1 and its receptor ErbB4, which are encoded by genes that are candidate susceptibility factors for schizophrenia (see SZGene for NRG1 and ErbB4).

From the labs of Oscar Marín and Beatriz Rico at Universidad Miguel Hernández in Sant Joan d’Alacant, Spain, the study in Nature finds that NRG1-ErbB4 signaling controls the wiring diagrams made by interneurons during brain development. The researchers localized the ErbB4 receptor to parvalbumin-containing interneurons in several regions of the brain. They further pinpointed ErbB4 to both the axon terminals and the dendrites of interneurons, and found that the receptor promotes synapse formation on both ends. Similar to other results (Vullhorst et al., 2009), the researchers did not turn up much evidence for NRG1-ErbB4 signaling in excitatory pyramidal neurons.

Beyond development, NRG1-ErbB4 signaling could modulate fully formed synapses, according to the January 19, 2010, PNAS paper from Lin Mei and colleagues at Medical College of Georgia in Augusta. The researchers found that application of NRG1 protein slowed action potential firing of excitatory pyramidal cells, and this dampening was likely mediated by ErbB4 receptors and the inhibitory neurotransmitter GABA found inside parvalbumin-containing interneurons. The researchers also found behavioral anomalies reminiscent of schizophrenia in mice lacking ErbB4 in parvalbumin-containing neurons.

Chandeliers and baskets
Parvalbumin, a calcium binding protein, marks a subset of interneurons that are fast-spiking cells, capable of sustaining rapid-fire action potentials. These types of interneurons have a hand in creating gamma waves, a kind of synchronized brain activity reported to be disrupted in people with schizophrenia (Spencer et al., 2003; see SRF hypothesis paper by Woo et al.). This connection to schizophrenia dovetails with an older line of research stemming from the postmortem observation of protein expression alteration in some populations of interneurons in cortex of people with schizophrenia (see SRF interview with David Lewis).

In their Nature paper, first author Pietro Fazzari and colleagues took a multi-pronged approach to pinpoint the location of NRG1-ErbB4 signaling to interneurons. Using mice engineered to have all their interneurons labeled with GFP, they first found that most ErbB4-expressing cells were, in fact, interneurons, and this pattern held for multiple cortical regions, including motor cortex, somatosensory cortex, visual cortex, and hippocampus. Next, they found that ErbB4 resided mainly in parvalbumin-containing neurons: for example, 85 percent of parvalbumin cells in the prefrontal cortex were also positive for ErbB4 expression, whereas only 10 percent of cells containing calretinin, a marker for a different class of interneuron, were positive for ErbB4. These ErbB4-positive neurons usually took on the distinctive shapes of chandelier and basket cells, which are fast-spiking interneurons. Finally, electron microscopy localized gold-tagged ErbB4 to the presynaptic boutons of interneurons contacting excitatory pyramidal cells, and to the post-synaptic densities along the dendrites of interneurons receiving excitatory input.

Fazzari and colleagues then found that NRG1-ErbB4 signaling promoted inhibitory synapse formation. Using electroporation to introduce genetic constructs to perturb NRG1-ErbB4 signaling during embryonic brain development, the researchers report that overexpressing NRG1 led to nearly twice as many GABA-containing boutons, whereas ablating ErbB4 decreased the density of boutons made by chandelier cells.

The researchers found that eliminating Erb4 specifically from interneurons in mice also translated into functional changes: pyramidal cells in the hippocampus of these mice received fewer spontaneous deliveries of GABA ("minis," in electrophysiologist lingo) than did those receiving input from interneurons containing ErbB4 from control mice. This suggests that an interneuron lacking ErbB4 has a pre-synaptic bouton that is not operating at full capacity. As for the post-synaptic side, interneurons lacking ErbB4 also received fewer minis from excitatory inputs than normal, and had a decreased density of glutamatergic terminals contacting them. Together, these results suggest that ErbB4 influences the intricacies of neural wiring during development via its role in the formation or maintenance of inhibitory synapses onto excitatory cells, or of excitatory synapses onto inhibitory cells.

A damper on excitement
Looking beyond development, the PNAS paper explored the function of NRG1-ErbB4 signaling on fully formed synapses. Prompted by their earlier work finding that NRG1 enhances GABA release in the cortex (Woo et al., 2007), Lin Mei's team examined the acute effects of NRG1 on excitatory pyramidal cells, which are contacted by interneurons. Sure enough, first author Lei Wen and colleagues found that adding NRG1 to brain slices made from the prefrontal cortex dampened activity—within five minutes—recorded from the excitatory pyramidal cells. The effect was dose dependent, with the highest dose of NRG1 reducing firing rates to 75 percent of normal levels. Blocking ErbB4 receptors or GABAA receptors prevented this effect, indicating that these receptors mediated NRG1's dampening action.

Because previous studies have placed ErbB4 inside parvalbumin-containing neurons (e.g., Fisahn et al., 2009), Wen and colleagues hypothesized that this type of interneuron was behind the NRG1-mediated decrease in pyramidal cell firing. To test this, they engineered mice in which ErbB4 was selectively eliminated from parvalbumin-containing neurons. NRG1 was no longer able to inhibit pyramidal neuron firing in brain slices made from these mice; similarly, NRG1 could no longer enhance the inhibitory synaptic currents received by pyramidal cells. These results suggest that NRG1 normally activates ErbB4 receptors in parvalbumin-containing interneurons, which then release more GABA onto pyramidal cells, reducing their activity.

The researchers also examined the behavior of mice lacking ErbB4 in parvalbumin-containing interneurons, and though they appeared normal in several respects, some schizophrenia-like features were detected. The mice were hyperactive, demonstrated poorer working memory in a radial arm maze task, and exhibited impaired paired-pulse inhibition—a measure of how much a startle response to a loud sound is diminished by a preceding tone. This deficit could be remedied with diazepam, a drug that enhances signals through GABA receptors, which is consistent with reduced inhibitory signaling in these mice.

Though both studies put interneurons at the center of NRG1-ErbB4 signaling in the brain both during development and afterwards, perturbations to inhibitory circuitry may well radiate out to disrupt other neurotransmitter systems. And because different brain regions probably consist of slightly different circuitries, future studies will have to settle the extent to which these new results hold in different brain areas. Overall, these studies continue the hard—yet crucial—work of examining how specific brain circuits are influenced by schizophrenia risk factors.—Michele Solis.

Fazzari P, Paternain AV, Valiente M, Pla R, Luján R, Lloyd K, Lerma J, Marín O, Rico B. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 2010 April 15.

Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, Yin DM, Lai C, Terry AV, Vazdarjanova A, Xiong WC, Mei L. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA. 2010 Jan; 107: 1211-1216. Abstract

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