Abstract
Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.
Highlights
Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons
We report the existence of alterations of dendritic spines in the nucleus accumbens and cocaine locomotor effects as early as 24 h after exposure of mice to a novel enriched environment (NEE)
A major protein bound to the DARPP-32 matrix, but not to casein, and eluted by 150 mM NaCl was identified as a mixture of a- and b-adducin (Supplementary Fig. 1a,b)
Summary
Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. Phospho-Thr75-DARPP-32 facilitates b-adducin Ser[713] phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Enriched environments alter behavioural effects of addictive drugs[5], little is known about the molecular mechanisms of such modulation of reward responses. The medium-sized spiny neurons of the striatum are major components of reward and motor systems and primary targets of dopamine innervation. These neurons express high levels of specific signalling proteins, including DARPP-32 (32-kDa dopamine- and cAMP-regulated phosphoprotein, protein phosphatase-1 regulatory subunit 1B (PPP1R1B)), a hub for several signalling pathways regulated by multiple extracellular signals[6,7]. Cocaine can induce phosphorylation of b-adducin by protein kinase C (PKC)[18] and mice lacking b-adducin show impairments in fear conditioning and spatial learning, and increased cocaine sensitization[14,15,16]
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