Abstract
Parkinson's disease (PD) is a multi-systemic neurodegenerative brain disorder. Motor symptoms of PD are linked to the significant dopamine (DA) loss in substantia nigra pars compacta (SNc) followed by basal ganglia (BG) circuit dysfunction. Increasing experimental and computational evidence indicates that (synaptic) plasticity plays a key role in the emergence of PD-related pathological changes following DA loss. Spike-timing-dependent plasticity (STDP) mediated by DA provides a mechanistic model for synaptic plasticity to modify synaptic connections within the BG according to the neuronal activity. To shed light on how DA-mediated STDP can shape neuronal activity and synaptic connectivity in the PD condition, we reviewed experimental and computational findings addressing the modulatory effect of DA on STDP as well as other plasticity mechanisms and discussed their potential role in PD pathophysiology and related network dynamics and connectivity. In particular, reshaping of STDP profiles together with other plasticity-mediated processes following DA loss may abnormally modify synaptic connections in competing pathways of the BG. The cascade of plasticity-induced maladaptive or compensatory changes can impair the excitation-inhibition balance towards the BG output nuclei, leading to the emergence of pathological activity-connectivity patterns in PD. Pre-clinical, clinical as well as computational studies reviewed here provide an understanding of the impact of synaptic plasticity and other plasticity mechanisms on PD pathophysiology, especially PD-related network activity and connectivity, after DA loss. This review may provide further insights into the abnormal structure-function relationship within the BG contributing to the emergence of pathological states in PD. Specifically, this review is intended to provide detailed information for the development of computational network models for PD, serving as testbeds for the development and optimization of invasive and non-invasive brain stimulation techniques. Computationally derived hypotheses may accelerate the development of therapeutic stimulation techniques and potentially reduce the number of related animal experiments.
Highlights
Spike-timing-dependent plasticity (STDP) is a fundamental mechanism in the brain that modifies the synaptic strengths between neurons based on the coincidence of pre- and postsynaptic spikes (Gerstner et al, 1996; Markram et al, 1997; Bi and Poo, 1998)
Following lesions of midbrain DAergic neurons in animal models of Parkinson’s disease (PD), it takes a couple of weeks for parkinsonian abnormal activity to emerge and stabilize in the external globus pallidus (GPe)-subthalamic nucleus (STN) circuit (Mallet et al, 2008b; Fan et al, 2012; Chu et al, 2015), suggesting that plasticity mechanisms may be involved in the emergence of longlasting pathological changes in the basal ganglia (BG) after DA loss (Day et al, 2006; Taverna et al, 2008; Fan et al, 2012; Chu et al, 2017) (for a review see (Chu, 2020))
Assuming that maladaptive plasticity following DA loss leads to the emergence of abnormal self-amplified structure-function interactions within the striatum and its down-stream pathways, one can hypothesize that the progressive emergence of excessively synchronized neuronal activity in GPe or STN in PD is simultaneously accompanied by abnormal reshaping of synaptic connectivity
Summary
Spike-timing-dependent plasticity (STDP) is a fundamental mechanism in the brain that modifies the synaptic strengths between neurons based on the coincidence of pre- and postsynaptic spikes (Gerstner et al, 1996; Markram et al, 1997; Bi and Poo, 1998). The presence of cholinergic and other GABAergic interneurons in the striatum can modify the intrinsic properties of MSNs (Shen et al, 2007), and in this way, affect the cortico-striatal transmission (Wang et al, 2006; Fino et al, 2008) Both direct and indirect pathways are under the influence of dopamine (DA) released from the SNc DAergic neurons (Calabresi et al, 2007; Surmeier et al, 2007; Pawlak and Kerr, 2008; Shen et al, 2008). We focus on the dynamical consequences of STDP as regards the stabilization of healthy or disease states To this end, we review a number of experimental observations on how DA depletion can trigger plasticity-induced maladaptive or compensatory processes at structural and dynamical levels, leading to dysfunction of different BG pathways.
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