Cell adhesion signaling pathways

Abstract

The 100 billion neurons comprising the human brain are wired together using structural extensions termed axons, dendrites, and dendritic spines. Addictive drugs remodel dendritic spine structure in certain brain regions, and with repeated exposure, induce psychomotor sensitization and impair behavioral flexibility. We recently reported that low-dose cocaine exposure, in combination with knockout of Arg—an adhesion-regulated nonreceptor tyrosine kinase that stabilizes neuronal shape starting in adolescence—recapitulates both features of chronic drug exposure in rodents. In light of these and other recent findings in the field, we suggest that cell adhesion receptors and their downstream cytoskeletal effectors act as “first responders” to psychostimulant exposure. In this model, cell adhesion factors act to stabilize existing dendritic spines in response to cocaine, and reduced expression/function is expected to increase vulnerability. Moreover, this model anticipates that increased sensitivity to psychostimulants in adolescence relates to neuronal pruning processes that occur during this developmental period.

Acknowledgements

Work in our laboratories is supported by PHS grants NS039475, CA133346 (A.J.K.) and DA011717 (J.R.T.); the Connecticut Department of Mental Health and Addiction Services (J.R.T.); and the Interdisciplinary Research Consortium on Stress, Self-control and Addiction (UL1-DE19586 and the NIH Roadmap for Medial Research/Common Fund, AA017537) (S.L.G., J.R.T., A.J.K.). AJK is also an Established Investigator of the American Heart Association.

Figures and Tables

Figure 1 Arg interacts with β-integrin tails and p190RhoGAP to stabilize synapses, spines and dendrites. Arg is activated through a physical interaction with intracellular β-integrin tails, which allows for p190RhoGAP phosphorylation and recruitment to the membrane by p120RasGAP. This complex inhibits RhoA GTPase activity. In the absence of RhoA inhibition, RhoA acts on ROCK to destabilize the actin cytoskeleton, leading to spine and dendrite collapse and synapse loss. Conversely, ROCK inhibition elongates dendritic branches.47

Figure 2 Arg deficiency confers vulnerability to cocaine and cocaine-induced deficits in a reversal task. (A) Arg-deficient mice show heightened psychomotor sensitivity to cocaine, as indicated by greater photobeams broken in a locomotor monitoring apparatus after low-dose (10 mg/kg, i.p.) cocaine administered across several days. Locomotor activity in the absence of cocaine is unchanged (not shown; 5,16). Because repeated breaking of the same photobeam constituted the largest difference between wt and arg^−/− mice, these specific counts (suggestive of stereotypy) are shown here. (B) During a reversal test in which mice must redirect responding from a previously reinforced operant aperture to a previously non-reinforced aperture, arg^−/− mice initially generate more “perseverative” errors than wild type (wt) counterparts (left), consistent with cortical dendritic simplification in these mice. arg^−/− mice acquired the reversal with repeated training (middle), but repeated exposure to low-dose cocaine greatly exacerbated perseverative errors (right), despite a prolonged washout period prior to test. *p ≤ 0.05; **p < 0.001.