The tumor suppressor PTEN regulates motor responses to striatal dopamine in normal and Parkinsonian animals

•Blocking PTEN reduces dopamine sensitivity of striatal neurons in culture.•Loss of bilateral striatal PTEN inhibits normal rat motor function.•Loss of striatal PTEN reduces D2-mediated rotations in Parkinsonian rats.•Dominant Akt activity overcomes striatal PTEN loss in vitro and in vivo.

Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.