Mechanisms of neuregulin 1 protection of excitatory neurons in stroke models

描述(申请人提供)：在美国，中风是导致死亡和成人残疾的主要原因。缺血会导致神经元和其他细胞的丧失，从而损害大脑功能。兴奋性神经元似乎对缺血特别敏感，而抑制性神经元似乎对缺血更具抵抗力。中间神经元对脑缺血的相对抵抗机制尚不清楚。神经调节蛋白1(NRG1)是一种营养因子，与神经发育和神经传递有关。有证据表明，它在缺血时兴奋性神经元的存活中起着关键作用。然而，潜在的机制还没有被很好地理解。最近的研究表明，NRG1可能通过刺激兴奋性神经元上的ErbB酪氨酸激酶发挥作用。或者，NRG1可以抑制炎性蛋白的表达，从而间接保护兴奋性神经元。在初步研究中，我们发现大脑中所有细胞中都没有ErbB4(NRG1受体)的突变小鼠更容易受到缺血性损伤，这表明在神经保护中发挥了关键作用。为了准确确定ErbB4可能在哪些神经元中发挥作用，我们另外产生了两个突变小鼠系：CaMKII-ErbB4-/-和PV-ErbB4-/-，其中ErbB4基因分别在兴奋性神经元和小白蛋白(PV)阳性的中间神经元中被特异性地去除。出乎意料的是，我们发现兴奋性神经元中的ErbB4是可有可无的，而PV阳性中间神经元中的ErbB4对于保护兴奋性神经元和抑制性神经元都是至关重要的。这些初步的 结果揭示了两个重要的含义。首先，NRG1可能通过激活PV阳性中间神经元中的ErbB4来间接保护兴奋性神经元。其次，它对缺血后PV阳性中间神经元的存活至关重要。为了验证这些假说，我们将研究ErbB4在NRG1对中风后兴奋性神经元保护中PV阳性中间神经元的作用，并确定NRG1是否以及如何保护缺血损伤后PV阳性中间神经元。这些结果将为深入了解NRG1/ErbB4信号如何保护缺血中的兴奋性神经元提供机制，并为未来识别潜在的卒中治疗干预靶点提供新的线索。

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and adult disability in the United States. Ischemia leads to loss of neurons and other cells, and thus impairs brain function. Excitatory neurons appear particularly vulnerable to ischemia, whereas inhibitory neurons appear more resistant to ischemia. The mechanisms underlying the relative resistance of interneurons to cerebral ischemia are unknown. Neuregulin 1 (NRG1) is a trophic factor that has been implicated in neural development and neurotransmission. Evidence suggests that it plays a critical role in excitatory neuronal survival in ischemia. Underlying mechanisms, however, are not well understood. Recent studies suggest that NRG1 may act by stimulating its receptor ErbB tyrosine kinases on excitatory neurons. Alternatively, NRG1 may inhibit expression of inflammatory proteins and thus indirectly protect excitatory neurons. In preliminary studies, we found that mutant mice without ErbB4, a NRG1 receptor, in all cells in the brain were more vulnerable to ischemic insult, suggesting a critical role in neuroprotection. To determine exactly in which neurons ErbB4 may act, we generated two additional lines of mutant mice: CaMKII-ErbB4-/- and PV-ErbB4-/- where the ErbB4 gene is ablated specifically in excitatory neurons and in parvalbumin (PV)-positive interneurons, respectively. Unexpectedly, we found that ErbB4 in excitatory neurons is dispensable whereas ErbB4 in PV-positive interneurons is critical for protecting excitatory as well as inhibitory neurons. These preliminary results reveal two important implications. First, NRG1 may protect excitatory neurons indirectly by activating ErbB4 in PV-positive interneurons. Second, it is crucial for the survival of PV-positive interneurons after ischemia. To test these hypotheses, we will investigate the role of ErbB4 in PV-positive interneurons in NRG1 protection of excitatory neurons in stroke and to determine whether and how NRG1 protects PV-positive interneurons after ischemic insult. The results will provide insight into mechanisms of how NRG1/ErbB4 signaling protects excitatory neurons in ischemia and provide new leads for future identification of targets for potential therapeutic intervention of stroke.