Figure 1.

Schematic representation of the main cellular and molecular processes responsible for PD pathogenesis, including neurotoxic agents entering SNpc DAergic neurons through the DA transporter (DAT). During the course of PD progression, functional alterations occur in this neuronal population due to changes in the biophysical properties of several ionic channels, like HCN channels, responsible for I_H, broad (BK) and small (SK) conductance Ca²⁺-dependent K⁺ channels, responsible for spike afterhyperpolarization (I_AHP) and ATP-dependent K⁺ channels. Alterations of the synaptic network also contribute to changes in membrane excitability involving glutamate and GABA transmission, as well as local D2 receptor-mediated auto-inhibition. Overall, these membrane mechanisms alter DAergic neurons’ resting membrane potential and firing discharge. Firing inhibition seems to characterize the initial stages of PD progression, possibly as an early defensive response against mitochondrial dysfunction, in order to preserve energy consumption. Conversely, later stages of PD progression appear to be mostly associated with an increase in membrane excitability, possibly in order to compensate for the loss of DA transmission, due to the ongoing neurodegenerative process eventually also affecting these hyperactive SNpc DAergic neurons.