Adaptive changes in striatal projection neurons explain the long duration response and the emergence of dyskinesias in patients with Parkinson’s disease

Abstract

Neuronal activity in the brain is tightly regulated. During operation in real time, for instance, feedback and feedforward loops limit excessive excitation. In addition, cell autonomous processes ensure that neurons’ average activity is restored to a setpoint in response to chronic perturbations. These processes are summarized as homeostatic plasticity (Turrigiano in Cold Spring Harb Perspect Biol 4:a005736–a005736, 2012). In the basal ganglia, information is mainly transmitted through disinhibition, which already constraints the possible range of neuronal activity. When this tightly adjusted system is challenged by the chronic decline in dopaminergic neurotransmission in Parkinson’s disease (PD), homeostatic plasticity aims to compensate for this perturbation. We here summarize recent experimental work from animals demonstrating that striatal projection neurons adapt excitability and morphology in response to chronic dopamine depletion and substitution. We relate these cellular processes to clinical observations in patients with PD that cannot be explained by the classical model of basal ganglia function. These include the long duration response to dopaminergic medication that takes weeks to develop and days to wear off. Moreover, dyskinesias are considered signs of excessive dopaminergic neurotransmission in Parkinson’s disease, but they are typically more severe on the body side that is more strongly affected by dopamine depletion. We hypothesize that these clinical observations can be explained by homeostatic plasticity in the basal ganglia, suggesting that plastic changes in response to chronic dopamine depletion and substitution need to be incorporated into models of basal ganglia function. In addition, better understanding the molecular mechanism of homeostatic plasticity might offer new treatment options to avoid motor complications in patients with PD.

Rostral Pedunculopontine Nucleus Infusion of M4Positive Allosteric Modulator VU0467154 Augments L-DOPA Effects in Hemiparkinsonian Rats

“…Even after two days of drug washout, forepaw stepping remained elevated in the Vehicle + Vehicle group. This is likely explained by long-term changes in the basal ganglia circuit which are caused by L-DOPA and which have been observed by others in the clinc (Albin & Leventhal, 2017;Cilia et al, 2020;Falkenburger et al, 2022) and in preclinical models (Kang & Auinger, 2012). This may mean that modulating PPN cholinergic activity may be efficacious as a strategy to augment L-DOPA effects in late-stage PD.…”

Serum neurofilament indicates accelerated neurodegeneration and predicts mortality in late-stage Parkinson’s disease

“…Furthermore, functional decline in PD may arise from the weakening of compensatory mechanisms rather than direct neurodegeneration. For instance, maladaptive plasticity in the striatum is believed to contribute to the development of dyskinesias and motor fluctuations 11 , 12 .…”

Motivational Vigor in Parkinson's Disease Requires the Short and Long Duration Response to Levodopa

“…The clinical response to the mainstay of PD treatment, L-dopa, is multifaceted, comprising a short duration response (SDR) paralleling plasma levels, and a long duration response (LDR) that slowly increments over the course of days to weeks and likely recedes after therapy cessation over similar timescales. [17][18][19][20][21][22][23] The LDR accounts for $60% of the total response to L-dopa. 23 The LDR is thought to account for the absence of motor fluctuations in early to moderate PD.…”