Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

Abstract

Most dendrite branches and a large fraction of dendritic spines in the adult rodent forebrain are stable for extended periods of time. Destabilization of these structures compromises brain function and is a major contributing factor to psychiatric and neurodegenerative diseases. Integrins are a class of transmembrane extracellular matrix receptors that function as αβ heterodimersand activate signaling cascades regulating the actin cytoskeleton. Here we identify integrin α3 as a key mediator of neuronal stability. Dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin α3 in excitatory forebrain neurons, reaching their mature sizes and densities through post-natal day 21 (P21). However, by P42 integrin α3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampus-dependent behavior. Furthermore, gene-dosage experiments demonstrate that integrin α3 interacts functionally with the Arg nonreceptor tyrosine kinase to activate p190RhoGAP (p190), which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior. Together our data support a fundamental role for integrin α3 in regulating dendrite arbor stability, synapse maintenance, and proper hippocampal function. In addition, these results provide a biochemical and structural explanation for the defects in LTP, learning, and memory previously reported in mice lacking integrin α3.

Digging a little deeper: The stages of invadopodium formation and maturation

“…The result is RhoC-ROCK-mediated LIMK activation and cofilin phosphorylation (inactivation) outside of invadopodia and active cofilin concentrated at the invadopodium core, where RhoC is inactive (Bravo-Cordero et al, 2011). Interestingly, β1 integrin induces Arg-dependent p190RhoGAP phosphorylation and activation in fibroblasts and neurons (Bradley et al, 2006; Kerrisk et al, 2013; Warren et al, 2012). Thus, it will be interesting to explore the possibility that β1 integrin-Arg signaling may act as a master upstream regulator of invadopodial cofilin activity through Arg-mediated phosphorylation of both cortactin on Y421 and p190RhoGAP at the invadopodia core to relieve cortactin- and RhoC-dependent suppression of cofilin activity, respectively.…”

Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase

“…Reductions in phospho-p190RhoGAP, as following CORT exposure, are associated with increased RhoA activity (Hernandez et al, 2004; Sfakianos et al, 2007; Warren et al, 2012; Kerrisk et al, 2013). Accordingly, we found that phosphorylation of cofilin, a major down-stream target of RhoA-ROCK signaling, is also increased following CORT.…”

“…Previous work from our group has identified an integrin-Abl2/Arg kinase-p190RhoGAP cascade that attenuates RhoA-ROCK signaling to stabilize hippocampal CA1 dendrite arbors (Moresco et al, 2005; Sfakianos et al, 2007; Warren et al, 2012; Kerrisk et al, 2013; Lin et al, 2013; Koleske, 2013). The current study provides evidence that CORT exposure disrupts this dendrite stabilization pathway.…”

ECM receptors in neuronal structure, synaptic plasticity, and behavior

“…There are 24 known integrin heterodimers of αβ subunits, and a subset of these are expressed in the brain, including in the hippocampus, cortex, thalamus, and cerebellum (Chan et al, 2003; Dansie and Ethell, 2011; McGeachie et al, 2011). In neurons, some integrins are enriched at synaptic membranes and localized to the postsynaptic density of dendritic spines (Bernard-Trifilo et al, 2005; Bourgin et al, 2007; Chavis and Westbrook, 2001; Kerrisk et al, 2013; Mortillo et al, 2012; Pinkstaff et al, 1999; Warren et al, 2012). In particular, integrin subunits α3, α5, α8, α(V), β1, and β3 function in a variety of roles in the brain, including neuronal migration, synapse and dendrite development, morphogenesis and stability, and synaptic plasticity (Gupton and Gertler, 2010; McCarty et al, 2005; Rehberg et al, 2014; Wu and Reddy, 2012).…”

“…Genetic disruption of integrin α3 from mice compromises hippocampal LTP, synapse and dendrite stability, and animal behavior (Chan et al, 2003, 2007; Kerrisk et al, 2013), but does not impact paired-pulse facilitation (PPF), a parameter sensitive to changes in presynaptic neurotransmitter release probability (Chan et al, 2003). Reducing the gene dosage of integrins α3 and α5 together is sufficient to cause defects in PPF, while simultaneous reduction of integrin α3, α5, and α8 gene dosage in a triple heterozygous animal yields defects in spatial memory and hippocampal LTP (Chan et al, 2003).…”