The onset of Parkinson’s disease is caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc) that project to DA-D1R and DA-D2R dopamine receptors on the dorsal lateral striatum. Over time, this neurodegeneration leads to a large decrease in striatal dopamine (DA) availability (A) and has large consequences in the direct and indirect pathways in the basal ganglia. In individuals affected by the disease, these changes in basal ganglial neurotransmission are characterized by motor symptoms such as bradykinesia (slowness of movement), tremor, gait dysfunction, rigidity, and postural instability as well as nonmotor symptoms such as losses in cognitive function and occurrence of mood disorders (D2). While a cure for Parkinson’s disease does not currently exist, recent research has been aimed toward the treatment of Parkinson’s disease through the induction of neuroprotective functions in the basal ganglia through several methods, including exercise.
Neurotransmission in the Normal and Parkinsonian Basal Ganglia
Neurotransmission through the basal ganglia is directed along two main pathways titled the direct and indirect pathways. While both pathways are stimulated by dopamine released from the SNc, the ultimate effects on downstream synapses are opposite. Whether the direct or indirect pathway is stimulated is determined by the whether dopamine binds to a DA-D1 or DA-D2 receptor on the striatum. The direct pathway is stimulated by the binding of dopamine to DA-D1R receptors on GABAergic neurons in the striatum. This stimulates the inhibitory release of GABA onto the substantia nigra pars reticulata (SNr) and medial globus pallidus (MGP). Neurons in these structures are also GABAergic, therefore, their inhibition means that they cannot release GABA onto downstream neurons in the thalamus. Neurons in the thalamus are thus disinhibited and able to release glutamate onto the cerebral cortex. The indirect pathway is stimulated by the binding of dopamine to DA-D2 receptors on a different set of GABAergic neurons in the striatum. This stimulates the inhibitory release of GABA onto the lateral globus pallidus (LGP) and the subsequent disinhibition of glutamatergic neurons in the subthalamic nucleus (STN). This ultimately leads to increased activity of GABAergic neurons in the SNr and MGP and inhibition of thalamic signaling to the cerebral cortex (I 70).
The impaired neurotransmission from the SNc to dopaminergic receptors on the striatum that occurs in Parkinson’s disease consequentially causes damage and functional impairment in downstream glutamatergic synapses projecting from the thalamus to the cerebral cortex (A, I70). This is expressed as damage or complete loss of basal ganglionic glutamatergic-based synaptic connections as well as increased activity of corticostriatal glutamatergic connections (A2, B2).
Low striatal dopamine levels cause a loss of homeostasis in the activity of the DA-D1R and DA-D2R dopamine receptor pathways. The DA-D1R direct pathway experiences decreased activity while the DA-D2R indirect pathway experiences increased activity.
Under normal conditions, DA controls the inhibition of the indirect pathway. Decreased DA availability leads to an increase in indirect pathway activity (E2). As mentioned above, the indirect pathway controls the inhibition glutamatergic signaling from the thalamus in the indirect pathway. A loss of inhibitory control over striatal GABAergic neurons causes a large release of GABA onto the GABAergic neurons in the LGP, causing a decrease in their activity. This leads the overactivation of glutamatergic STN neurons. This causes increased activity of GABAergic neurons in the MGP that send information to the thalamus, thus causing glutamate levels in the synaptic clefts between neurons of the thalamus and cerebral cortex to increase. This alteration in synaptic transmission ultimately causes a change in the premotor cortex input levels (E2).
DA controls excitatory control of the direct pathway. Decreased dopamine levels lead to decreased excitation of the direct pathway, which is normally responsible for the release of GABA onto the MGP. Without this excitatory control, GABAergic neurons that project from the MGP to the thalamus are overactivated. These changes affect premotor and motor output sent through the corticostriatal pathway to the basal ganglia (E2).
Treatment of Parkinson’s Disease through Induction of Neuroprotective Qualities
While the process of the degeneration of dopaminergic neurons in the dorsal laterals striatum remains unknown, it is likely that the process includes many various mechanisms including mitochondrial defects, oxidative stress, glutamate toxicity, apoptosis, genetic factors, and neuroinflammation (I71, J32). Recently, methods to control these mechanisms have been explored protect and prevent the death of these neurons and serve as a treatment for Parkinson’s disease.
While glutamate is necessary in the normal transmission of excitatory signals, increased glutamate release that occurs as a result of reduced activation of DA-D2R’s leads to excitotoxicity (I71). Elevated levels of glutamate lead to the overactivation of N-methyl-D-aspartate receptors (NMDARs) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) on MSNs. This causes disinhibition of voltage-gated ion channels and large influxes of Ca2+ that overload downstream neurons (C4). Large Ca2+ influx into a neuron’s can lead to increased levels of oxidative stress (mediated by mitochondria) through the synthesis of nitric oxide and the activation of Ca2+-dependent enzymes that are used to catabolize proteins, nucleic acid, and phospholipids. This affects neurons is many ways, such as altering the cytoskeleton, synthesis of nitric-oxide derived free radicals, and breakdown of the cell membrane, all ultimately resulting in cell death (I 72). Furthermore, it has been shown that the expression of voltage-gated Ca2+ channels in the cerebral cortex of Parkinson’s patients is increased (J30). This information indicates that the regulation of glutamate transmission as well as the maintenance of Ca2+ homeostasis as potential targets of neuroprotection in Parkinson’s.
Research has shown that overactive glutamate transmission in MPTP-lesioned mice can be altered through exercise. Results showed that exercise increased the expression of Ca2+-impermeable AMPAR’s in relation to Ca2+-permeable AMPAR’s on striatal MSN’s, thus causing a decrease in synaptic excitability and post-excitatory synaptic potentials. It was also shown that exercise decreased the amount of glutamate that was stored in presynaptic cells (glutamatergic neurons). These results illustrate that exercise is able to reduce excitation by glutamate and enable transmission in the cortico-striatal circuit (D5, D6).
Another possible mechanism contributing to the etiology of Parkinson’s disease is mitochondrial dysfunction. Aggregations of misfolded alpha synuclein protein and increased levels of glutathione are two widely known contributors to the inhibition of mitochondrial complex I. Alpha synuclein protein normally acts to recycle synaptic vessels and modulate the transmission of dopamine within neurons in the substantia nigra. When mutations within the alpha synuclein gene cause the alpha synuclein protein to be misfolded, the protein accumulates within mitochondria, forming Lewy body structures within the neurons. This causes an increase in the production of reactive oxygen species (ROS) and causes impaired functioning of complex 1, which subsequently decreases cellular respiration and ATP production within dopaminergic neurons. As a result, acute inhibition of complex I has been shown to cause neuronal cell death. Since PD patients exhibit reduced activity and expression of complex I in dopaminergic neurons in the SN, the aggregation of mutated alpha synuclein is a likely contributor the development of PD (K1, K8). Furthermore, the onset of mitochondrial dysfunction is thought to be an effect of oxidative stress (J 31). Therefore, it is possible that mitochondrial dysfunction is both an effect and contributor to oxidative stress (through increased production of ROS).
Research has shown that depletion of substantia nigral glutathione, and essential antioxidant, leads to the inhibition of mitochondrial complex I and degeneration of nigrostriatal dopaminergic neurons (J31, L2). Research on antioxidant systems has shown that moderate exercise causes some oxidative stress that leads to the synthesis of glutathione through the activation of nuclear factor erythroid 2-related factor (Nrf2)-regulated antioxidant systems. Nrf2 is a transcription factor that controls the synthesis of gamma glutamylcysteine ligase (gamma GCL), the rate-limiting enzyme in the synthesis of glutathione. Therefore, its activation leads to increased levels of glutathione available to combat oxidative stress.
After a four-week treadmill exercise-training regimen implemented after induction of PD symptoms through MPP+ toxicity, data showed that Nrf2/gamma GCL expression was activated. The training was also shown to prevent the loss of function of the Nrf2 antioxidant system and the death of dopaminergic neurons. Since mice with MPTP-induced Parkinson’s symptoms showed decreased expression of Nrf2-regulated genes, it is possible that Nrf2 is a key factor in the maintenance of normal glutathione levels and the control of ROS-induced oxidative stress contributing to the pathogenesis of Parkinson’s (L2, L9).
The DA-D1R and DA-D2R pathways control the cortico-striatal motor circuit and frontal-striatal circuit, which are responsible automatic movement, volitional movements (D2). Due to fast decline in levels of DA in the dorsal lateral striatum, Parkinson’s disease causes a loss in individuals’ ability to perform automatic routine movements to appear even during early stages. The loss of automatic movement, normally controlled by the cortico-striatal circuit, results in a possible shift of motor control onto the frontal-striatal circuit. This means that movements once performed automatically will require conscious effort for successful execution (D3). In addition, the cortico-striatal and frontal-striatal circuits, as well as the DA-D1Rs and DA-D2Rs, are required for the aquisitional phase of motor learning and the cortico-striatal circuit and the DA-D2R pathway is necessary for the retention phase of motor learning (D3). Loss of coordination of these pathways, therefore, could lead to deficits in the acquisition and retention of motor learning and thus contribute to symptoms experienced by Parkinson’s patients.
In addition to motor deficits, changes that occur within lead to impairment of cognitive processes such as executive function, which includes working memory, problem solving, task-flexibility, planning tasks, and execution of tasks as well as mood disorders (D2). Parkinson’s causes non-motor symptoms of anxiety, depression, disturbance in sleep, gastrointestinal dysfunction, anosmia, and sympathetic denervation (G1).
By inducing a deficiency in VMAT2, (responsible for vesicular transport of monoamines such as dopamine) in animals, researchers are able to induce monoaminergic dysfunction, shown through progressive loss of dopamine in the striatum as well as diminished norepinephrine (NE) and 5-HT (serotonin). This deficiency also causes a loss of nigral dopaminergic neurons, motor deficits, and alpha synuclein accumulation (G1, G2).
The induction of neurotoxicity through administration of 6-OHDA and MPTP-lesioning causes impaired function in the basal ganglia as well as DA depletion as well as the subsequent losses in behavioral motor abilities (A3). The utilization of many types of exercise regimens including voluntary wheel running, treadmill, and forced exercise has shown that neuroprotective properties can be activated through altered expression of dopamine markers such as vesicular transporter type-2 (VMAT-2) and dopamine transporter (DAT) as well as increased dopaminergic neuron survival (as analyzed through neuron-count and striatal dopamine and metabolite levels) (A4). When performed prior to or within a week post-lesioning, forced practice of intense motor tasks was shown to activate protection of dopaminergic neurons and retention of motor skill behavior. Induction of neuroprotection is thought to be owed to increased levels of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which aid neurons’ ability to grow and survive (A4). While measuring BDNF mRNA levels in rats, voluntary activity level and BDNF mRNA levels were found to be positively correlated (F).
Another possible cause for neuroprotection could lie in the altered expression of DAT and VMAT-2, which are normally involved with uptake and store the toxic form of MPTP as well as the 6-OHDA neurotoxin. Voluntary wheel training also suggested that altered expression of VMAT-2 and DAT lead to induction of neuroprotection against MPTP-lesioning in dopaminergic neurons in the midbrain. Mechanistic similarities between MPTP-lesioning and 6-OHDA and environmental toxins commonly attributed to the onset of PD suggest that altered concentrations of DAT and VMAT-2 induced by exercise may cause protection by reducing dopaminergic neurons’ exposure to such neurotoxins (A4).
In another study, a relationship was found between the depressive-like behavior and reduced BDNF levels in 6-OHDA treated animals. It was found that animals that had undergone physical training displayed reductions in depressive-like behavior as well as increased levels of striatal and hippocampal neurotrophins (BDNF and its precursors). Since BDNF moderates synaptic development and neuroplasticity, it is suggested that increased levels of BDNF produced by physical exercise promote plasticity and prevent neuronal cell death, thus decreasing the occurrence of depressive-like behavior. Increased BDNF levels were shown for animals that had undergone forced swimming, open-field locomotor activity, and rotational tests. Therefore, it was suggested that the intensity of the exercise, rather than the type of exercise, is the most important factor in inducing neuroprotective benefits (M4, M5, M6).
In addition to its contribution to oxidative stress, the accumulation of alpha synuclein protein is thought to cause neuroinflammation through the activation of Toll-like receptor-2 (TLR2)-mediated signaling cascades. When TLR2 recognizes the alpha synuclein protein, it activates the production of toxic pro-inflammatory cytokines TNF-alpha and IL-1beta, inducing inflammation and promoting dopaminergic cell death (N1). When MPTP-treated mice were put through endurance exercise training, it was found that the endurance exercise improved motor performance to the level achieved pre-MPTP treatment, suppressed alpha synuclein to the pre-treatment level, and inhibited TLR2 signaling cascades, preventing neuroinflammation. It is suggested that the suppression of alpha synuclein through endurance exercise leads to decreased TLR2 signaling, thus initiating an anti-inflammatory effect that protects neurons from degradation (N2).
Research performed with human subjects has also provided information that possibly links exercise and protection against neurodegeneration. When comparing long-term group exercise performed by adults with PD, results showed a correlation between exercise and improvement of symptoms affecting motor control and decreased cognitive decline. These results are possibly linked to mechanisms within the central nervous system (CNS) that protect neurons by reducing inflammation (H6).
Data from this study also demonstrated that individuals who began long-term group exercise for two 24-week time periods self-reported significantly fewer depression symptoms than individuals who only participated for one 24-week period. This supports data showing that performing a greater amount of exercise leads to less fatigue and is correlated with reduced apathy and depression in Parkinson’s patients (H7).
I. Provide a perspective on how/whether this information should be used to shape physical therapy regimen design for patients suffering from Parkinson’s disease in the future.
Notes: Is there a distinction between cortical and thalamic synapse regulation.