Synaptic plasticity, dopamine and Parkinson's disease: one step ahead

The progressive loss of substantia nigra pars compacta neurons that characterizes Parkinson's disease pathology leads to impaired levels of dopamine in several key structures of the basal ganglia neuronal circuit and subsequent alteration of the thinly regulated balance between activities of the output nuclei—the internal segment of the globus pallidus and the substantia nigra pars reticulata —that is considered essential for normal function of the circuit (Fig. 1A). Fig. 1 The basal ganglia circuit. Potential implications of the LTP of GABAergic signals onto substantia nigra pars reticulata neurons. ( a) During physiological conditions the thinly regulated activity of the direct and indirect pathways controls the activity of the output nuclei. ( b ) During Parkinson's disease, in the absence of a pharmacological treatment, dopamine deficiency causes overactivity of the indirect pathway and reduced activity of the inhibitory GABAergic direct pathway, disinhibiting the output nuclei and thus causing excessive inhibition of the motor thalamus. In this condition, high frequency stimulation does not induce a lasting change in GABAergic field potential amplitude in the substantia nigra pars reticulata . ( c ) After the administration of l-DOPA, the same high-frequency stimulation protocol induces potentiation of the GABAergic field potential amplitudes, reducing the excessive inhibitory activity that the output nuclei exert on the motor thalamus. ( d ) Finally, after the chronic administration of l-DOPA, uncontrolled potentiation of the GABA-mediated inhibition of the output nuclei might result in long-term suppression of their firing rate which in turn might lead to pathological disinhibition of the thalamus and the subsequent onset of pathological hyperkinetic behaviours, such as l-DOPA-induced dyskinesias. Note that, in the Figure, inhibitory GABAergic connections are represented in red, excitatory glutamatergic connections in green and dopaminergic connections in black.Although many advances have been made in the field of Parkinson's disease research, the precise mechanisms leading to symptom …