Mechanisms of neuregulin 1 protection of excitatory neurons in stroke models

描述（由申请人提供）：中风是美国成年人死亡和残疾的主要原因。缺血导致神经元和其他细胞的丧失，从而损害脑功能。兴奋性神经元似乎对缺血特别脆弱，而抑制性神经元似乎对缺血更有抵抗力。中间神经元相对抵抗脑缺血的机制尚不清楚。神经调节蛋白1 （NRG1）是一种参与神经发育和神经传递的营养因子。有证据表明，它在缺血时兴奋性神经元的存活中起关键作用。然而，其潜在机制尚不清楚。最近的研究表明NRG1可能通过刺激其受体ErbB酪氨酸激酶对兴奋性神经元起作用。或者，NRG1可能抑制炎症蛋白的表达，从而间接保护兴奋性神经元。在初步研究中，我们发现在大脑所有细胞中缺乏ErbB4（一种NRG1受体）的突变小鼠更容易受到缺血性损伤，这表明其在神经保护中起关键作用。为了准确确定ErbB4可能在哪些神经元中起作用，我们产生了另外两种突变小鼠系：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切除。出乎意料的是，我们发现兴奋性神经元中的ErbB4是必不可少的，而pv阳性中间神经元中的ErbB4对于保护兴奋性和抑制性神经元至关重要。这些初步

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. PUBLIC HEALTH RELEVANCE: The proposal is to 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 o stroke.