As observed in Parkinson's disease, loss of dopamine (DA) within the nigrostriatal pathway in rodents due to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), results in alterations in the glutamate input to the striatum and substantia nigra (SN). Following MPTP, there is a decrease in the basal glutamate levels in the striatum and an increase in the SN 56,84. Glutamate receptor antagonists decrease the locomotor deficits associated with the loss of striatal DA. Exposure of mice to an enriched environment (EE) for 2 months prior to the administration of MPTP results in a reduced loss of tyrosine hydroxylase (TH) immunolabeled neurons in the substantia nigra pars compacta (SN-PC) compared to the MPTP-treated animals exposed to the standard environment (SE) 6. We are the first to report that 1 week following subchronic MPTP, continuous exposure to an EE for the next 21 days, with continued MPTP administration, partially restores the loss of TH-labeled neurons in the SN-PC compared to the MPTP/SE group. This also results in improvement in motor function. In young mice, subchronic MPTP administration results in a 50% loss of TH-labeled neurons in the SN-PC and a 30% increase in their dependence upon a vertical support when rearing in a cylinder (ie wall assisted vs unassisted rears). In aged mice, subchronic MPTP results in a 45% loss of TH-labeled cells in the SN-PC and a nearly 60% increase in the number of wall-assisted vs unassisted rears. Comparing aged versus young mice, following exposure to an EE only, there is 1.) a 25% increase in the basal levels of extracellular striatal glutamate (~95% in young mice), 2.) no change in the density of nerve terminal glutamate immuno-gold labeling (25% decrease in young mice), 3.) no change in the striatal protein level for the glial protein, GFAP (65% increase in young mice), and 4.) a 29% increase in the protein levels for the glutamate transporter, GLT-1 (10% increase in young mice). There is a trend towards an increase in the dopamine transporter protein following an EE in both young and aged mice. Therefore, increased striatal glutamate may be a mechanism by which an EE reduces the loss of TH-labeled neurons in the SN-PC and promotes motor recovery. Another possible mechanism we will test is whether an EE is having an affect directly on glutamate and gamma-aminobutyric acid (GABA) synapses in the SN. The overall goal of this proposal is to investigate the effects of subchronic MPTP, age and exposure to an EE on alterations in glutamate in both the striatum and SN. GABA levels will also be measured in the SN. The overarching hypothesis of this proposal is that the effects of MPTP on striatal and SN glutamate will be partially reversed by exposure to an EE, leading to partial recovery of motor behavior, DA levels in the striatum and partial restoration of TH-labeled cells in the SN-PC. This reversal will occur in the aged mice, but it will be greater in younger compared to the aged mice.
The specific aims of this proposal are to 1.) determine the effects of age (10 weeks vs 12 months) and dosing of the toxin on changes in striatal glutamate, TH-labeled cells in the SN-PC, and motor behavior after 1 week of subchronic administration of MPTP, followed by continuous exposure to an EE, 2.) determine the effect of subchronic MPTP-induced changes in striatal glutamate, TH-labeled cells in the SN- PC and motor behavior after exposure to an EE for either 2 or 6 hours/day, and 3.) determine the effects of subchronic administration of MPTP, followed by continuous exposure to an EE, on changes in both glutamate and GABA in the SN and motor behavior in young versus aged mice. We will further determine if blockade of SN glutamate receptors or increasing striatal glutamate following MPTP will both mimic the affect of exposure to an EE.
Investigation of movement disorders, especially Parkinson's disease, is a high priority research area within the Department of Veterans Affairs. Because of the high incidence of this disease in the general population over the age of 50 and the fact that the age of the veteran population is slowly increasing, this movement disorder is affecting more and more of our veterans. Since exposure to an enriched environment in at least non-Parkinsonian patients and in an animal model of this disease appears to be effective in terms of augmenting motor and cognitive behavior, this type of non-pharmacological approach needs further investigation. The results from this project have potentially wide implications of great significance to the population cared for by the Department of Veteran Affairs and by the fact that six Parkinson's Disease Research, Education and Care Centers (PADRECCs) currently are funded (one here at the Portland VA Medical Center), to carry out clinical research projects focusing on Parkinson's disease.