Spike-Timing-Dependent Plasticity Mediated by Dopamine and its Role in Parkinson’s Disease Pathophysiology

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.

Inhibitory Spike-Timing-Dependent Plasticity Can Account for Pathological Strengthening of Pallido-Subthalamic Synapses in Parkinson’s Disease

“…Abnormal strengthening of GPe-STN synapses was experimentally attributed to motor cortical-driven heterosynaptic long-term potentiation (hLTP) resulted from interactions between the hyperdirect and indirect pathways ( Chu et al, 2015 , 2017 ). However, findings in animal PD models have revealed that the knockdown of STN NMDARs prevents the strengthening of GPe-STN synapses ( Chu et al, 2015 ), suggesting that classical NMDAR-dependent LTP may be involved in this process ( Madadi Asl et al, 2022 ).…”

“…For example, both the cortex-striatum-GPe-STN and cortex-STN inputs were simply simulated as constant currents and there was no interactions between the BG, cortex and thalamus. Our model may not be able to capture the complex network interactions within the cortico-BG-thalamic circuits leading to pathological structure and dynamics in PD ( Madadi Asl et al, 2022 ), but still can reproduce fundamental biophysical mechanisms related to pathological activity-connectivity patterns in the GPe-STN network, which is considered as the main rhythmogenesis center within the cortico-BG-thalamic network ( Plenz and Kital, 1999 ; Bevan et al, 2002 ; Holgado et al, 2010 ).…”

“…Motor impairment in PD is accompanied by the emergence of excessive neuronal synchronization and abnormal beta band (15–30 Hz) oscillations in the external segment of globus pallidus (GPe) and subthalamic nucleus (STN) ( Kühn et al, 2006 ; Hammond et al, 2007 ; Mallet et al, 2008a ; Neumann et al, 2017 ; Asadi et al, 2022 ), that together may play the role of a pacemaker in the basal ganglia (BG) circuitry ( Plenz and Kital, 1999 ; Bevan et al, 2002 ; Holgado et al, 2010 ). Abnormal rhythmogenesis in the recurrently connected GPe-STN network occurs following the cascade of structural and functional changes after dopamine (DA) loss ( Day et al, 2006 ; Moran et al, 2011 ; Fan et al, 2012 ; Miguelez et al, 2012 ; Lemos et al, 2016 ; Chu et al, 2017 ; Madadi Asl et al, 2022 ). This ultimately leads to the dysfunction of cortico-BG-thalamo-cortical (CBGTC) loop, as implicated in several movement disorders ( DeLong and Wichmann, 2007 ).…”

“…However, synaptic plasticity may play a role in the pathological strengthening of GPe-STN synapses following DA depletion; for a comprehensive review see Madadi Asl et al (2022) . First, altered striato-pallidal ( Day et al, 2006 ; Lemos et al, 2016 ) and pallido-pallidal ( Miguelez et al, 2012 ) synaptic transmission can reduce GPe-STN activity ( Magill et al, 2001 ; Mallet et al, 2012 ), resulting in an elevated activation of STN N-methyl-D-aspartate receptors (NMDARs) which further promotes the strengthening of GPe-STN inputs ( Chu et al, 2017 , 2015 ).…”

“…It is shown that STDP can lead to the emergence of bistable dynamical states due to the coevolution of activity-connectivity patterns ( Aoki and Aoyagi, 2009 ; Gilson et al, 2009 ; Madadi Asl et al, 2018a ) which computationally relate to normal and parkinsonian network dynamics ( Madadi Asl et al, 2022 ), i.e., physiological states (weak synchrony, weak connectivity) as opposed to pathological states (strong synchrony, strong connectivity) ( Popovych and Tass, 2012 ; Lourens et al, 2015 ; Madadi Asl et al, 2018c ). When STDP mediates the evolution of the network connections, the correlated neurons that causally fire together in a synchronized manner (with small time difference between their spikes) form stronger synapses than those uncorrelated neuronal groups that fire with large time differences in a desynchronized manner which is due to the competitive nature of STDP ( Song et al, 2000 ).…”