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.