Figure 1.

Behavioral-metabolic synergy model explaining physiology (A) and pathophysiology (B) of the nigrostriatal complex. The model clarifies how neurodegeneration of the nigrostriatal complex may be initiated in the striatum. In physiological conditions, the synergy is critically dependent on both dopaminergic input from the substantia nigra pars compacta (SNPC), and GABAergic network of the striatal input. The subventricular zone (SVZ) is a specialized brain area containing self-renewing population of progenitor cells that continuously replace fast spiking interneurons (FSIs) in the dorsal striatum. The process allows to maintain input threshold of the striatum limiting neuronal activity of the basal ganglia. Deficient neurogenesis within the SVZ may contribute to a decline in the nigrostriatal synergy resulting in progressive withdrawal and eventually disconnection of the dopaminergic input. Such deficiency initiates a “vicious circle” cascade of pathological events resulting in a devastating decline of nigrostriatal synergy that leads to a fatal damage to striatal input that in turn intensifies neurodegeneration of the DOPA neurons of the SNPC. In this state, the striatum loses its control over the pallidal output and several motor symptoms such as tremor, rigidity, and bradykinesia can be observed. The model reproduced with permission from Błaszczyk (2017). Copyright 2017 Acta Neurobiologia Experimentalis. Please note that within CNS the behavior-metabolic synergy has a form of repeatable sequence of intracellular biochemical processes triggered by neuronal action potentials. Such sequence must always be concluded by the process(es) of metabolic energy recovery in mitochondria. Deficit in energy metabolism may result in faulty neuronal activity increasing risk of apoptosis. In this context, impoverished SNPC activity e.g., due to natural ageing, pathology and/or reduced motor activity (hipokinesia) do potentiate neurodegeneration within the nigrostriatal system.