ARP2/3 complex has a neuroprotective role and is required for mature dendritic spine head morphology

Abstract

Several lines of evidence suggest that Arp2/3 may play a role in regulating dendritic spine morphology. First, inhibition of the Arp2/3 activators N-WASP, Cortactin, and Wave alters spine morphology and density (Racz and Weinberg 2004, Pipel and Segal 2005, Soderling et al. 2007b, Wegner et al. 2008). Second, electron microscopy of dendritic spines revealed that the actin filaments within the spine head appear to be organized in "Y" shaped branches (Fifkova and Delay 1982). Since, Arp2/3 is the only complex known to make "Y" branched actin filaments, the presence of such branches in spine heads strongly suggests that Arp2/3 is involved in actin polymerization in spines. Consequently, the general hypothesis for my doctoral work is that if Arp2/3 is a major regulator of dendritic spine morphology, then Arp2/3 will be enriched in dendritic spines heads and inhibition of Arp2/3 activity will alter the number and/or morphology of dendritic spines. Our results show Arp2/3 localization within the dendritic spine heads of cultured hippocampal neurons. However, we observed Arp2/3 redistribution within dendritic shafts in response to induced synaptic activity. Temporal inhibition of Arp2/3 function during dendritic spine development showed severe morphological consequence in mature cultures. Finally, in collaboration with Dr. Robert Meller of Dow Neurobiology Laboratory at Legacy Research, Legacy Health in Portland Oregon, we show that Arp2/3 has a neuroprotective role of in ischemia tolerance.