Dopamine depletion underlies the symptoms of Parkinson’s disease (PD) by driving plastic changes in the striatum’s populations of dopamine D1 receptor (D1R)-expressing and dopamine D2 receptor (D2R)-expressing spiny projection neurons (SPNs). Toxic forms of alpha-synuclein (α-Syn) play various causal roles in PD. However, because SPNs do not express α-Syn, the possible effect of α-Syn on striatal microcircuitry and pathophysiology has been overlooked. We have shown that α-Syn drives morphological changes in corticostriatal (CS) axons that impair excitatory striatal input. Here, we will characterize how α-Syn in CS fibers differentially affects the innervation of D1 vs. D2 SPNs both morphologically and in terms of presynaptic and postsynaptic physiological properties. Furthermore, both D1Rs and D2Rs can activate the PI3K/AKT/mTOR pathway, which we have recently shown is perturbed by toxic α-Syn. We will test whether toxic α-Syn in CS axons impacts pre- & postsynaptic D1R vs. D2R activation of this pathway. We hope to show for the first time that:1) α-Syn can directly and differentially affect D1 and D2 SPNs independently before the appearance of the effects of dopamine denervation; and that 2) specific drugs, designed to inhibit the PI3K/AKT/mTOR pathway, can restore the balance between the direct and indirect pathways in PD.