ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disease whose hallmark pathological features include a selective loss of dopaminergic neurons in the midbrain. Recent studies have described the activation of a stress-induced signal cascade, c-Jun N-terminal kinase (JNK)-mediated activation of c-Jun, and an increase in the expression of a downstream effector, cyclooxygenase 2 (COX-2), in postmortem PD brains. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces selective neuronal loss in the midbrain similar to that seen in PD, also induces JNK-mediated activation of c-Jun and generates a COX-2 response in C57BL/6J mice. However, mice exhibit a strain-dependent susceptibility to MPTP. Identifying the point(s) of molecular divergence in the MPTP-induced response may provide insight into the cause of PD or a means to identify susceptibility to PD in humans. Here we examined JNK signaling and COX-2 induction in two strains of mice, the MPTP-sensitive C57BL/6J and the MPTP-resistant Swiss Webster (SW). We show that C57BL/6J and SW strains differ in JNK and c-Jun activation in response to MPTP. In addition, the MPTP-induced COX-2 response occurs exclusively in C57BL/6J mice. Furthermore, strain-specific responses to MPTP are not due to differences in MPP(+) levels and are not secondary to cell death. These results provide evidence toward a mechanism of strain-dependent sensitivity to MPTP.
Subject(s)
Cyclooxygenase 2/metabolism , Drug Resistance/genetics , JNK Mitogen-Activated Protein Kinases/metabolism , Nerve Degeneration/enzymology , Parkinsonian Disorders/enzymology , Substantia Nigra/enzymology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Animals , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Nerve Degeneration/chemically induced , Nerve Degeneration/physiopathology , Neurons/drug effects , Neurons/enzymology , Neurons/pathology , Neurotoxins/pharmacology , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Proto-Oncogene Proteins c-jun/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Species Specificity , Substantia Nigra/drug effects , Substantia Nigra/physiopathologyABSTRACT
Idiopathic Parkinson's disease (PD) affects 2% of adults over 50 years of age. PD patients demonstrate a progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that recapitulates the pathology of PD is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we show that exposure to an enriched environment (EE) (a combination of exercise, social interactions and learning) or exercise alone during adulthood, totally protects against MPTP-induced Parkinsonism. Furthermore, changes in mRNA expression would suggest that increases in glia-derived neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g. dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contribute to the observed neuroprotection of dopamine neurons in the nigrostriatal system following MPTP exposure. This non-pharmacological approach presents significant implications for the prevention and/or treatment of PD.
Subject(s)
Environment , Nerve Degeneration/physiopathology , Neurons/pathology , Parkinsonian Disorders/physiopathology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism , Analysis of Variance , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cell Count/methods , Cell Death/physiology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Glial Cell Line-Derived Neurotrophic Factor , Immunohistochemistry/methods , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , MPTP Poisoning/metabolism , MPTP Poisoning/physiopathology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice , Mice, Inbred C57BL , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Parkinsonian Disorders/pathology , RNA, Messenger/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Tyrosine 3-Monooxygenase/metabolism , Vesicular Biogenic Amine Transport Proteins , Vesicular Monoamine Transport ProteinsABSTRACT
Exposure to an enriched environment (EE), consisting of a combination of increased exercise, social interactions and learning, has been shown to produce many positive effects in the CNS. In this study, we use a Golgi-Cox analysis to examine and dissect the role of various components of the enriched environment on two measures of neuronal growth: total cell volume and total dendritic length in four regions of the brain. In the hippocampus, CA1 and dentate gyrus cells, animals raised in an enriched environment demonstrate significant morphological change. These changes were not observed in layer V pyramidal neurons of the cerebral cortex or spiny neurons located in the striatum. To determine if one or more of the individual components of the EE were responsible for the changes in neuronal morphology, we examined mice raised with free access to exercise wheels. In these mice, no morphological changes were observed. These results suggest that changes in the CA1 and dentate gyrus morphology were a result of alterations in the animal's environment and not an increase in motor activity.
Subject(s)
Cell Differentiation/physiology , Dendrites/ultrastructure , Environment, Controlled , Sensory Deprivation/physiology , Telencephalon/cytology , Telencephalon/growth & development , Animals , Animals, Newborn , Cell Size/physiology , Cerebral Cortex/cytology , Cerebral Cortex/growth & development , Cerebral Cortex/physiology , Dendrites/physiology , Dentate Gyrus/cytology , Dentate Gyrus/growth & development , Dentate Gyrus/physiology , Exploratory Behavior/physiology , Hippocampus/cytology , Hippocampus/growth & development , Hippocampus/physiology , Male , Mercuric Chloride , Mice , Mice, Inbred C57BL , Neostriatum/cytology , Neostriatum/growth & development , Neostriatum/physiology , Physical Conditioning, Animal/physiology , Potassium Dichromate , Social Behavior , Telencephalon/physiologyABSTRACT
In utero exposure to cocaine has been shown to affect dopaminergic populations of developing neurons in the central nervous system (CNS). To determine if this was a regionally specific effect or the result of a global phenomenon, we used a Golgi-Cox analysis to measure several parameters of neuronal development in murine neurons from frontal cortex, a region of the cortex containing monoamine innervation, and somatosensory cortex, a monoamine sparse part of the cortex. Results of these analyses show that in utero exposure to cocaine affects total dendrite length in histotypical layers III and IV and dendritic volume in layer III of the frontal cortex. These effects are not present in the somatosensory cortex.
