Distinct Roles of the β1-Class Integrins at the Developing and the Mature Hippocampal Excitatory Synapse

Abstract

Integrins are a large family of cell adhesion receptors involved in a variety of cellular functions. To study their roles at central synapses, we used two cre recombinase lines to delete the Itgb1 ␤1 integrin gene in forebrain excitatory neurons at different developmental stages. Removal of the ␤1 integrins at an embryonic stage resulted in severe cortical lamination defects without affecting the cellular organization of pyramidal neurons in the CA3 and CA1 regions of the hippocampus. Whereas the hippocampal neurons underwent normal dendritic and synaptic differentiation, the adult synapses exhibited deficits in responses to high-frequency stimulation (HFS), as well as in long-term potentiation (LTP). Deletion of ␤1 integrin at a later postnatal stage also impaired LTP but not synaptic responses to HFS. Thus, the ␤1-class integrins appear to play distinct roles at different stages of synaptic development, critical for the proper maturation of readily releasable pool of vesicles during early development but essential for LTP throughout adult life.

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

“…Similarly, antagonists of the ryanodine or IP3 receptors controlling SER release markedly depressed ligand effects on [Ca 2+ ]i. Together, the concentration of integrins at spine synapses (Nishimura et al, 1998;Huang et al, 2006;Shi and Ethell, 2006;Webb et al, 2007) and the contribution of SER stores to changes in [Ca 2+ ]i provide some understanding of the spatio-temporal pattern of the latter effect. RGD-induced increases in [Ca 2+ ]i appeared first in dendrites and tens of seconds later in somata.…”

“…This list includes integrins directly implicated in calcium regulation by the present findings: treatment with activating anti-α5ß1 or with fibronectin, a ligand for all four integrins, increased [Ca 2+ ]i. Interestingly, this list corresponds with that for integrins implicated in adult hippocampal LTP. Genetic (Chan et al, 2006;Huang et al, 2006) or immunochemical (Kramár et al, 2006) disruption of ß1 integrin function blocks the stabilization of hippocampal LTP whereas manipulation of the individual α3, α5, or α8 subunits has similar but more modest effects (Chun et al, 2001;Kramár et al, 2002;Chan et al, 2003). The fact that greater disruptions to LTP, and memory, are observed when the α subunits are manipulated in combination (i.e., in mutant mice underexpressing combinations of α3, α5 and α8, or in rat tissue treated with a cocktail of neutralizing antisera to α3, α5, and αv) (Chan et al, 2003; suggests that these integrins make additive contributions to processes supporting LTP, including increases in postsynaptic calcium content (Lynch et al, 1983;Rose and Konnerth, 2001).…”

“…These subunits define the two major families of integrins expressed in brain (Milner and Campbell, 2002); ß1-containing integrins are of particular interest because they modulate glutamatergic synaptic transmission Bernard-Trifilo et al, 2005) and plasticity (Kramár et al, 2002;Chan et al, 2003;Chan et al, 2006;Huang et al, 2006;Kramár et al, 2006). The effects of the integrin ligands and antisera on perikaryal [Ca 2+ ]i as assessed over time and at the initial peak RGD-induced increase for three experimental sets are summarized in figure 2.…”

“…Although integrins lack direct kinase activity, ligand binding initiates conformational changes and signaling through tyrosine kinase and Rho GTPase initiated cascades (Miranti and Brugge, 2002;Schwartz and Ginsberg, 2002;DeMali et al, 2003;Bernard-Trifilo et al, 2005). Recent evidence indicates that brain integrins are concentrated at synapses, modulate excitatory transmission , and play a critical role in the stabilization of Long-Term Potentiation (LTP) (Staubli et al, 1990;Staubli et al, 1998;Chun et al, 2001;Chan et al, 2006;Huang et al, 2006;Kramár et al, 2006;Nagy et al, 2006;Meighan et al, 2007;Wang et al, 2007), a form of synaptic plasticity widely thought to underlie learning (Morris, 2003;Lynch et al, 2007). How brain integrins contribute to the production of stable LTP is poorly understood.…”

Regulation of AMPA receptors and synaptic plasticity

“…Integrins are TM heterodimers of ␣-and ␤-subunits (Giancotti and Ruoslahti, 1999;Coppolino and Dedhar, 2000;Schwartz and Shattil, 2000;van der Flier and Sonnenberg, 2001) and have been recently directly implicated in hippocampal LTP (Chan et al, 2006;Huang et al, 2006;Kramar et al, 2006). Infusion of an integrin ligand (the peptide GRGDSP) into rat hippocampal slices reversibly increased the slope and amplitude of excitatory postsynaptic potentials mediated by AMPARs (Kramar et al, 2003).…”