Neuroprotection by ErbB4 in parvalbumin-positive interneurons in stroke

Stroke is a leading cause of death and adult disability in the United States. Ischemia in stroke leads to loss of excitatory as well as inhibitory neurons, and thus impairs brain function. 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, I 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, I 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, I 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 correlative 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, I will investigate the role of ErbB4 in PV-positive interneurons in NRG1 protection of excitatory neurons in stroke and will determine whether and how NRG1 protects PV-positive interneurons after ischemic insult. Results of this study will provide insight into mechanisms of how NRG1/ErbB4 signaling protects excitatory neurons in ischemia. It may reveal a novel function of NRG1 to protect PV-positive interneurons and regulate their function in ischemia and reveal new leads for future studies and eventual identification of targets for potential therapeutic intervention (AHA Program: Postdoctoral Fellowship)