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Neuregulin-ErbB4 Signaling in Parvalbumin Interneurons: Implications for Schizophrenia and Epilepsy

16 December 2011. Signaling through neuregulin 1 (NRG1) and its receptor ErbB4 on parvalbumin (PV)-expressing neurons regulates PV neuron excitability and has an anti-epileptogenic effect, according to two studies published online December 11 in Nature Neuroscience. In addition to the clear implications for the epilepsy field, these studies may also provide insight into the pathophysiology of schizophrenia, in which both NRG1 and ErbB4 have been implicated as key players (see SRF related news story).

The studies, one from Xiao-Ming Li’s group in Zhejiang University in China and the other from the groups of Lin Mei at Georgia’s Health Sciences University, Augusta, and Zhi-Qi Xiong at the Chinese Academy of Sciences in Shanghai, probe the role of NRG1-ErbB4 signaling in rodents. NRG1 is a neurotrophic factor that binds to and activates the receptor tyrosine kinase ErbB4. Both are prominent in fast-spiking PV interneurons (see SRF related news story), involved in a variety of developmental processes and altered in schizophrenia (Mei and Xiong, 2008). For example, both NRG1 and ErbB4 are candidate susceptibility genes, and altered levels of both mRNAs and proteins have been reported in the illness (Chong et al., 2008; see also SRF related news story).

PV interneuron excitability
First author Ke-Xin Li and colleagues found that NRG1-ErbB4 signaling regulates the excitability of PV neurons. Using recordings from PV neurons in both cortical and hippocampal slices from mice, the authors observed that bath application of NRG1 decreased the average interspike interval and increased the firing frequency of PV neurons. These effects were blocked by the application of ecto-ErbB4, a peptide that blocks the action of NRG1 by preventing it from activating endogenous receptors.

In order to assess whether NRG1 modulates the excitability of PV neurons directly or acts by modulating inputs to these neurons, the researchers blocked synaptic inputs using glutamate and γ-aminobutyric acid (GABA) receptor antagonists. In the presence of these drugs, the effects of NRG1 and ecto-ErbB4 remained, suggesting that NRG1 directly affects the intrinsic properties of PV neurons. Moreover, the effect of NRG1 on PV neuron excitability was mediated by ErbB4, as there was no effect of NRG1 in mice with a selective knockout of ErbB4 in PV neurons.

Further investigation revealed that NRG1 increased the slope of action potential initiation in PV neurons, and shifted the threshold for action potentials to more hyperpolarized levels, but did not affect passive membrane properties. The voltage shift was mediated by the voltage-gated potassium channel Kv1.1, evidenced by the fact that treatment with the Kv1.1 blocker DTx-K prevented the normal ecto-ErbB4-mediated increase in current threshold and decrease in firing frequency. Using current subtraction analysis, the authors found that ecto-ErbB4 doubled the DTx-K-sensitive current amplitude, implying that NRG1 normally dampens this Kv1.1 current. This was mediated via phosphorylation, as phosphotyrosine levels increased after NRG1 treatment.

The study suggests that changes to PV neuron excitability could be one manifestation of alterations in the NRG1-ErbB4 signaling pathway in schizophrenia. This is especially relevant, given that PV neurons are known to exhibit other alterations in schizophrenia, including lower levels of both the GABA-synthesizing enzyme GAD67 and PV itself (Hashimoto et al., 2003), and because a disturbance in the balance of excitation and inhibition also produces schizophrenia-like behaviors (see SRF related news story).

Seizure prevention
Li and colleagues also showed that mice lacking ErbB4 in PV neurons have an increased susceptibility to seizures in two different models of epilepsy (using either GABA antagonist pentylenetetrazole, or the muscarinic agonist pilocarpine to induce seizures), and that treatment with NRG1 ameliorated seizures. Additionally, the authors found that ErbB4 protein levels are reduced in individuals with temporal lobe epilepsy.

In the second study, Xiong’s group showed that NRG1-ErbB4 signaling in PV neurons, but not pyramidal neurons, suppressed limbic epileptogenesis. Using both the kindling model of epilepsy, in which animals are repeatedly given an electrical stimulus that produces progressively more intense and longer seizures, as well as the pilocarpine model, first author Guo-He Tan and colleagues observed an increase in NRG1 mRNA and protein after seizures in both rats and mice. In contrast, total ErbB4 protein levels were unchanged.

Next, the authors evaluated the effect of NRG1 on seizures using the kindling model, and found that infusion of NRG1 prior to each electrical stimulation resulted in a significant delay of epileptogenesis, while infusing ecto-ErbB4 promoted it. Similar to the neuronal excitability results of Li and colleagues, Xiong’s group also observed that the anti-epileptogenic properties of NRG1 require the receptor ErbB4, as treatment with an ErbB4 inhibitor promoted epileptogenesis.

The suppressing effect of NRG1 on seizure activity seems to be specific to PV interneurons. In mice with a specific knockout of ErbB4 in PV neurons, the team observed accelerated epileptogenesis; however, mice with a knockout of ErbB4 in pyramidal neurons did not show this effect (although NRG1 treatment in these animals did inhibit epileptogenesis).

NRG1 and ErbB4: linking schizophrenia and epilepsy?
Interestingly, there seems to be a relationship between schizophrenia and epilepsy. Having epilepsy (or a family history of the disease) is associated with increased risk for developing schizophrenia or schizophrenia-like psychosis (Foong, 2006). Conversely, some epilepsy patients also exhibit psychotic symptoms (Cascella et al., 2009). Both studies elucidated mechanisms that may underlie schizophrenia and epilepsy, and together, strengthen the link between the two diseases.—Allison A. Curley.

Li KX, Lu YM, Xu ZH, Zhang J, Zhu JM, Zhang JM, Cao SX, Chen XJ, Chen Z, Luo JH, Duan S, Li XM. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci . 2011 Dec 11. Abstract

Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci . 2011 Dec 11. Abstract

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