The emerging role of integrins in neuropsychiatric disorders

Disrupted physical and functional associations between neurons are thought to govern the abnormal patterns of neural signaling that underlie neuropsychiatric disorders. As membrane signaling proteins that bridge extracellular interactions and intracellular signaling, integrins have been well studied for their role in cell migration, cell adhesion, and metastasis, but have been relatively underexplored for their contribution to mental illness and pharmacotherapy. Integrins are obligate α- and β-heterodimers that display molecular heterogeneity, as well as developmental and regional regulation (Denda and Reichardt, 2007). Early in development, integrin signaling supports developmental events such as neuronal migration and synaptic differentiation. Integrins also contribute to the plasticity of mature synapses. In turn, both integrin expression and signaling are sensitive to drug and pathophysiological manipulation of synapses. For example, integrin subunit expression is differentially altered by acute and chronic cocaine administration (Wiggins et al, 2009). Such alterations are likely to be functionally important, as integrin expression can influence neuronal recovery after injury, a capacity that depends on the interaction of integrins with growth factor receptors and cytokines. Several integrins have been associated with neuropsychiatric disorders, raising the possibility that they represent important new targets for medication development. Recently, we provided evidence that integrins containing the β3-subunit (ITGB3) influence the serotonin system through, in part, a direct interaction with the serotonin transporter (SERT, SLC6A4) (Carneiro et al, 2008, AM Carneiro and RD Blakely, unpublished results). These findings provide a physical basis for multiple studies that have reported associations of both ITGB3 and SLC6A4 (and gene × gene interactions) with autism risk. The SERT/β3 complex may provide an important framework for SERT regulation that likely relies on the clustering of integrins and integrin-associated proteins. Thus, targetting this complex may prove fruitful in rectifying altered serotonergic signaling in multiple neuropsychiatric disorders. In addition, integrin-αVβ3 modulates glutamatergic signaling in the CNS. Activation of αVβ3 by ligand binding leads to selective activation of MAPK-linked signaling pathways (Watson et al, 2007), as well as plasma membrane trafficking of AMPA-type glutamate receptors (Cingolani et al, 2008). These changes alter synaptic scaling, leading to alterations in the long-term potentiation of neuronal signaling. Further studies will no doubt seek to extend these findings to determine their relationship to behaviors such as learning and memory. Nonselective peptide ligands and novel subunit-specific ligands are used to pursue the role of integrins in neuronal function. Integrin-β3 ligands are based on the Arg-Gly-Asp sequence present in the binding domain of extracellular matrix proteins. Cyclic Arg-Gly-Asp peptides show nanomolar αVβ3 affinities, whereas isoxazoline compounds (currently under clinical trials) show femtomolar affinities (Miller et al, 2000). Although these compounds were initially developed for in vivo mapping of malignant tumors and cancer treatment, they also provide exciting leads for reagents that can target αVβ3-specific pathways in neurons. Furthermore, they provide a platform for developing blood–brain barrier penetrant ligands that can probe in vivo contributions of integrin signaling to behavior and possibly novel treatments for devastating brain disorders.