Altered AMPA receptor expression with treadmill exercise in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse model of basal ganglia injury

Abstract

Dopamine depletion leads to impaired motor performance and increased glutamatergic-mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In the present study, we investigated the effect of high-intensity treadmill exercise on changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input-output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine-sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline-treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.

Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice

“…This supports the hypothesis that exercise may selectively rebalance the functioning of the basal ganglia to permit L-DOPA to partially restore dopaminergic tonus without development of LID. This contention is further supported by the ability of exercise to prevent the development of the cardinal neurochemical changes in the basal ganglia that are known to be associated with LID (Liste et al, 1997, Aguiar et al, 2010, VanLeeuwen et al, 2010.…”

“…This would be a tight analogy with the ability of exercise to attenuate memory impairment in Parkinsonism (Aguiar et al, 2009), which involves a growth factor mediated (reviewed in Cotman and Berchtold, 2002). An alternative hypothesis would be an impact of exercise on the glutamatergic afferents driving the basal ganglia, in accordance with the impact of exercise on the morpho-functional plasticity of glutamatergic synapses (Real et al, 2010, VanLeeuwen et al, 2010 that are known to be affected in dyskinetic animals (Kobylecki et al, 2010, Sgambato-Faure andCenci, 2012).…”

“…Along with L-DOPA, exercise can also stimulate and normalize motor function in animal models of PD (Aguiar et al, 2009, VanLeeuwen et al, 2010. In particular, exercise reduces stereotypic movements (Klusha et al, 1983, Dey and Singh, 1992, Teixeira et al, 2008, the phosphorylation of DARPP-32 (Aguiar et al, 2010) and the expression of c-Fos in the murine striatum (Liste et al, 1997).…”

Does vigorous exercise have a neuroprotective effect in Parkinson disease?

“…Exercise attenuates the hyperexcitability of striatal (medium spiny) neurons after dopamine depletion, with modulation of glutamatergic receptor subunit expression. 54 Notably, vigorous exercise in these parkinsonian animal models induces brain neurotrophic factor expres-sion, which may mediate putative neuroprotective effects. This includes brain-derived neurotrophic factor (BDNF) 47 and glial-derived neurotrophic factor (GDNF).…”

Strategies to encourage physical activity in patients with Parkinson's disease: improving quality of life

“…40 Changes in glutamatergic neurotransmission induced via exercise, including changes in glutamate and glutamatergic receptor families such as NMDA or AMPA, are well-established, critical components of neuroplastic changes by altering glutamate release, glutamate receptor expression, which leads to attenuation of glutamatergic hyperexcitability. [41][42][43] These alterations help restore normal synaptic plasticity of the neurodegenerative basal ganglia, resulting in restoration of motor behavior. 44,45 Collectively, these studies demonstrate that alterations in dopaminergic and glutamatergic neurotransmission modulate corticostriatal hyperexcitability, which in turn leads to improvement of exercise-induced behavior.…”