Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease☆
Introduction
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of midbrain dopaminergic neurons leading to the depletion of striatal dopamine (DA). Individuals with PD manifest both cognitive and motor deficits including balance instability, gait dysfunction, slowness, tremor, and rigidity. While DA replacement therapy remains a cornerstone of treatment, its efficacy diminishes over time. Currently, there is no known cure for PD. A major interest of research in PD is to find treatments that have the capacity to modify disease progression or better prevent disease onset. For example, epidemiological studies have suggested that intensive exercise, especially in males, over a lifetime can influence the occurrence of PD (Chen et al., 2005). Over the last decade a number of investigators have demonstrated exercise to be beneficial for the treatment of PD especially for the treatment of gait and balance (Petzinger et al., 2010, Petzinger et al., 2013, Speelman et al., 2011). In animal models of PD, exercise has been shown to have the capacity to be both neuroprotective, by preventing the loss of DA in lesion models (Gerecke et al., 2010), and neurorestorative, providing enhancement in DA neurotransmission leading to reversal of motor deficits (Fisher et al., 2004, Petzinger et al., 2007). These observations, along with ongoing basic and clinical research, are beginning to investigate the potential role of exercise in modifying disease progression in individuals with PD as well as in animal models of DA-depletion. Towards this goal, a major focus of our lab has been to elucidate the underlying molecular mechanisms by which exercise affects neuroplasticity including synaptic structure and function within the injured basal ganglia in neurotoxin animal models of PD.
In PD and in neurotoxin animal models, the depletion of striatal DA leads to alterations in basal ganglia neurotransmission that manifest in a number of different ways. For example, the striatopallidal (indirect) projection medium spiny neurons (MSNs) become hyperactive and are thought to underlie the onset of akinesia (slowness of movement) (Calabresi et al., 1997). In addition, corticostriatal projections targeting striatal MSNs also display aberrant glutamatergic neurotransmission as demonstrated through electrophysiological techniques (Cepeda et al., 1989, Pisani et al., 2005). Therefore, it is not surprising that striatal MSNs manifest these changes in neurotransmission by alterations in the dendritic spine number and dendritic arborization, the primary morphological correlates of synaptic neurotransmission. For example, studies using Golgi staining have shown a reduction in dendritic arborization and spine density in the caudate nucleus and putamen in tissues from patients with PD (McNeill et al., 1988, Stephens et al., 2005). Similar findings have been made in both the 6-hydroxydopamine (6-OHDA) rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nonhuman primate models of DA-depletion where spine density changes have been reported (Ingham et al., 1989, Ingham et al., 1993, Villalba and Smith, 2010).
The purpose of this study was to determine if intensive exercise in the form of treadmill running leads to a reversal of both dendritic spine loss and the reduction in dendritic arborization in a mouse model of DA-depletion. This speculation is largely based on the fact that we observe exercise enhanced alterations in both glutamate and DA neurotransmission in the MPTP-lesioned mouse model (Kintz et al., 2013). Since dendritic spine density and branching are influenced by experience including environmental enrichment and exercise in several regions of the mammalian brain we were interested in knowing if exercise leads to a similar outcome (Comery et al., 1995, Eadie et al., 2005, Leggio et al., 2005, Stranahan et al., 2007). We also took advantage of the Drd2-eGFP-BAC transgenic mouse strain (Chan et al., 2012, Nelson et al., 2012) in conjunction with biocytin injection methods that allowed us to delineate dopamine D1 receptor (DA-D1R)-containing MSNs and dopamine D2 receptor (DA-D2R)-containing MSNs since some models of DA-depletion show preferential loss of dendritic spine density selectively on DA-D2R-containing MSNs (Day et al., 2006). Utilizing the MPTP mouse model of DA-depletion with either Golgi staining or biocytin labeling we examined the effects of 6 weeks of intensive treadmill running on dendritic spine density and arborization of MSNs within the dorsolateral striatum, a region responsible for motor control and a site where we have documented neuroplastic changes in response to exercise (Petzinger et al., 2007).
Section snippets
Animals
Twelve C57BL/6J young adult (8 to 10 weeks old) male mice from Jackson Labs (Bar Harbor, Maine) and 52 young adult (8 to 10 weeks old) male Drd2-eGFP-BAC mice (Tg(Drd2-EGFP)118Gsat/Mmnc) supplied by the Mutant Mouse Regional Resource Center of NIH (MMRRC) program at the University of California, Davis (Gong et al., 2003) were used for this study. We have established a colony of Drd2-eGFP-BAC mice that have been backcrossed into C57BL/6J mice in our lab at least 10 times to enhance genomic
MPTP administration leads to loss of striatal DA
In the non-exercised Drd2-eGFP-BAC mice, striatal DA was significantly reduced (p = 0.002) at 5 days post-lesioning by 88.2% in MPTP (43.8 ± 8.5 ng/mg protein ± SEM) compared to saline mice (372 ± 38) and still significantly reduced (p = 0.001) at 42 days post-lesioning by 86.3% in MPTP (57.4 ± 5.7) compared to saline mice (419 ± 27) (Fig. 1). In the exercised Drd2-eGFP-BAC mice, striatal DA was significantly reduced at 42 days post-lesioning by 86.0% in MPTP + exercise (50.7 ± 10.2) compared to saline + exercise mice
Discussion
Intensive treadmill exercise results in an increase in overall dendritic spine density within the striatum of the MPTP mouse model. DA-depletion led to a decrease in spine density of both DA-D1R- and DA-D2R-containing MSNs of the direct and indirect pathways, respectively, while exercised mice did not show this loss in either pathway. Treadmill running has been shown to increase dendritic spine density within the striatum in a hemorrhagic stroke model in the rodent (Takamatsu et al., 2010);
Conclusion
In conclusion, this study demonstrates an exercise induced increase in dendritic spine density and arborization in an animal model of PD. Increased expression of proteins involved in synaptic connectivity observed in the MPTP mouse model may contribute to exercise related benefits in motor skill learning and performance in the DA-depleted state. Future studies will examine if changes in spine morphology are associated with alterations in the electrophysiological properties of striatal MSNs and
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Grant information: The authors would like to acknowledge the support of the NINDS RO1 NS44327, the U.S. Army NETRP (Grant # W81XWH-04-1-0444), the Zumberge Foundation of USC, the Southern California Clinical and Translational Science Institute and the University of Southern California, Keck School of Medicine RR031986. Special thanks to Friends of the USC Parkinson's Disease Research Group including George and Mary Lou Boone, Walter and Susan Doniger, Edna and John Ball, Team Parkinson, Team 4BA, and the family of Don Gonzalez Barrera.