D1 and NMDA receptor interplay in physiological and pathological conditions : focus on Parkinson's disease

Functional and structural interactions between D1 receptor (D1R) and NMDA receptor (NMDAR) have been shown to play a critical role in many functions of the brain. Interestingly, when these subtle interactions become abnormal, they might contribute to several diseases.Here we show that prolonged activation of D1R by SKF 38393 is able, in vitro as well as in vivo, to significantly reduce the quantity of NR2A subunit at the postsynaptic site. Interestingly, this molecular effect was in agreement with the reduction in the NMDA-AMPA ratio and specifically in NMDA(NR2A)-AMPA ratio as demonstrated by electrophysiological recordings. Considering the effect of this pharmacological approach on the NMDA subunit composition, we used SKF38393 in a model of “early” Parkinson's Disease (PD), the so called “partial lesion” model. In this condition, mild motor impairments were observed, compared to the more severe alterations occurring in the full lesion model. In addition, in corticostriatal slices recorded from partial lesioned animals (PL) a lack of Long Term Potentiation (LTP) was found, as well as a strong increase in the NR2A subunit abundance at the postsynaptic site. In the attempt to restore synaptic plasticity in PL, SKF38393 was administered in vivo. Surprisingly, the treatment successfully restored LTP in striatal neurons, by reducing the NR2A subunit levels at the postsynaptic site and it improved the motor performances. Finally, in order to avoid the typical side effects deriving from the dopaminergic treatment in PD, we used an alternative tool able to mimic the effect of the D1 agonist on the NMDAR subunit composition. To this end, we directly targeted NMDAR via a cell permeable peptide, TAT2A, acting towards the interruption of the NR2A subunit delivery to the NMDAR complex. Notably, TAT2A determined a significant improvement in motor behaviour and it rescued LTP thus representing a new therapeutic strategy in PD