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Dietary restriction affects striatal glutamate in the MPTP-induced mouse model of nigrostriatal degeneration
Haley K Holmer1, Modjgan Keyghobadi, Cynthia Moore
1Research Services, Neurocytology Lab, V.A. Medical Center, Portland, Oregon 97239, USA.
Abstract:
One month following subchronic treatment with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg/d x 7 days), there is a decrease in the extracellular level of striatal glutamate. It has been reported that following dietary restriction (DR) (fed on alternate days) of C57BL/6 mice, MPTP administration resulted in a reduction in the loss of tyrosine hydroxylase-positive neurons within the substantia nigra pars compacta (SN-PC) compared to the ad libitum (AL)-fed MPTP-treated mice. However, there have been no reports of whether the MPTP-induced alterations in brain neurochemistry or morphology can be similarly attenuated by DR if initiated after administration of the toxin. In the MPTP/AL group there is a decrease in the extracellular level of striatal glutamate compared to the Vehicle/AL group. However, 21 days of DR starting 1 day after the last subchronic dose of MPTP results in a reversal in the extracellular level of striatal glutamate compared to the MPTP/AL group. DR alone resulted in a decrease in extracellular striatal glutamate. There was no change in the relative density of the glutamate transporter, GLT-1, within the striatum or SN-PC between any of the groups, suggesting that the alterations in striatal extracellular glutamate were not due to a change in this specific transporter. There was an increase in the density of nerve terminal glutamate immunolabeling in the MPTP/AL and MPTP/DR groups compared to the Vehicle/AL group. There was a similar decrease in the relative density of tyrosine hydroxylase immunolabeling within the striatum and the SN-PC in both the MPTP/AL and MPTP/DR groups compared to the Vehicle/AL group. Since a decrease in the activity of the corticostriatal glutamate pathway has been reported in both Parkinson's disease and in animal models of nigrostriatal loss, these data suggest that DR initiated after the partial loss of striatal dopamine appears to reverse the decrease in striatal glutamate.
Insights
Dietary restriction (DR) initiated after MPTP toxin exposure reversed decreased striatal glutamate levels in mice. This suggests DR may mitigate neurochemical changes in Parkinson's disease models even after initial damage.
Area of Science:
- Neuroscience
- Neuropharmacology
- Neurochemistry
Background:
- Subchronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treatment causes striatal glutamate decrease.
- Dietary restriction (DR) can protect against MPTP-induced neuronal loss if applied before toxin exposure.
Purpose of the Study:
- To investigate if DR initiated after MPTP administration can reverse MPTP-induced neurochemical alterations.
- To examine the effects of post-toxin DR on striatal glutamate levels and dopamine markers.
Main Methods:
- Mice received MPTP or vehicle, followed by either ad libitum (AL) feeding or DR (alternate-day feeding).
- Extracellular striatal glutamate levels and GLT-1 transporter density were measured.
- Tyrosine hydroxylase (TH) and nerve terminal glutamate immunolabeling were assessed.
Main Results:
- MPTP/AL mice showed decreased striatal glutamate compared to controls.
- Post-MPTP DR reversed the decrease in striatal glutamate.
- DR alone decreased striatal glutamate.
- No changes in GLT-1 density were observed.
- Both MPTP/AL and MPTP/DR groups showed reduced TH-positive neurons, indicating nigrostriatal damage.
Conclusions:
- Dietary restriction initiated after MPTP exposure can reverse alterations in striatal glutamate levels.
- These findings suggest DR may be a therapeutic strategy for Parkinson's disease, even after dopamine neuron loss.
- Glutamate transporter GLT-1 is not the primary mechanism behind these observed glutamate level changes.
