A critical role for GM1 ganglioside in the pathophysiology and potential treatment of Parkinson's disease.

Parkinson's disease (PD) is slowly progressing neurodegenerative disorder that affects millions of patients worldwide. While effective symptomatic therapies for PD exist, there is no currently available disease modifying agent to slow or stop the progression of the disease. Many years of research from various laboratories around the world have provided evidence in favor of the potential ability of GM1 ganglioside to be a disease modifying agent for PD. In this paper, information supporting the use of GM1 as a disease modifying therapeutic for PD is reviewed along with information concerning the role that deficiencies in GM1 ganglioside (and potentially other important brain gangliosides) may play in the pathogenesis of PD.

NYX-458 Improves Cognitive Performance in a Primate Parkinson's Disease Model.

BACKGROUND: NYX-458 is a N-methyl-d-aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD. OBJECTIVES: NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms. METHODS: NYX-458 was evaluated in the chronic low-dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with low-dose or high-dose levodopa to assess potential impact on motor symptoms. RESULTS: NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia. CONCLUSIONS: NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Altered genome-wide hippocampal gene expression profiles following early life lead exposure and their potential for reversal by environmental enrichment.

Early life lead (Pb) exposure is detrimental to neurobehavioral development. The quality of the environment can modify negative influences from Pb exposure, impacting the developmental trajectory following Pb exposure. Little is known about the molecular underpinnings in the brain of the interaction between Pb and the quality of the environment. We examined relationships between early life Pb exposure and living in an enriched versus a non-enriched postnatal environment on genome-wide transcription profiles in hippocampus CA1. RNA-seq identified differences in the transcriptome of enriched vs. non-enriched Pb-exposed animals. Most of the gene expression changes associated with Pb exposure were reversed by enrichment. This was also true for changes in upstream regulators, splicing events and long noncoding RNAs. Non-enriched rats also had memory impairments; enriched rats had no deficits. The results demonstrate that an enriched environment has a profound impact on behavior and the Pb-modified CA1 transcriptome. These findings show the potential for interactions between Pb exposure and the environment to result in significant transcriptional changes in the brain and, to the extent that this may occur in Pb-exposed children, could influence neuropsychological/educational outcomes, underscoring the importance for early intervention and environmental enrichment for Pb-exposed children.

Sex-based differences in gene expression in hippocampus following postnatal lead exposure.

The influence of sex as an effect modifier of childhood lead poisoning has received little systematic attention. Considering the paucity of information available concerning the interactive effects of lead and sex on the brain, the current study examined the interactive effects of lead and sex on gene expression patterns in the hippocampus, a structure involved in learning and memory. Male or female rats were fed either 1500 ppm lead-containing chow or control chow for 30 days beginning at weaning.Blood lead levels were 26.7±2.1 µg/dl and 27.1±1.7 µg/dl for females and males, respectively. The expression of 175 unique genes was differentially regulated between control male and female rats. A total of 167 unique genes were differentially expressed in response to lead in either males or females. Lead exposure had a significant effect without a significant difference between male and female responses in 77 of these genes. In another set of 71 genes, there were significant differences in male vs. female response. A third set of 30 genes was differentially expressed in opposite directions in males vs. females, with the majority of genes expressed at a lower level in females than in males. Highly differentially expressed genes in males and females following lead exposure were associated with diverse biological pathways and functions. These results show that a brief exposure to lead produced significant changes in expression of a variety of genes in the hippocampus and that the response of the brain to a given lead exposure may vary depending on sex.

Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment.

A parkinsonian syndrome can be produced in nonhuman primates by administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Parkinsonian-like symptoms induced acutely by MPTP were ameliorated after treatment with GM1 ganglioside, a substance shown to have neurotrophic effects on the damaged dopamine system in rodents. Treatment with GM1 ganglioside also increased striatal dopamine and metabolite levels and enhanced the dopaminergic innervation of the striatum as demonstrated by tyrosine hydroxylase immunohistochemistry. These results suggest that GM1 ganglioside may hold promise as a therapeutic agent for the treatment of Parkinson's disease.

A major direct GABAergic pathway from zona incerta to neocortex.

Retrograde fluorescent tracers were used to demonstrate a previously unknown but sizable direct gamma-aminobutyric acid (GABA)-containing neuronal pathway from the zona incerta to the neocortex in rats. This incertocortical pathway was found to project bilaterally to the entire neocortex and exhibited a rough corticotopic organization. Many of the zona incerta neurons projecting to the parietal and occipital cortices could also be immunohistochemically stained with antibodies to glutamic acid decarboxylase and GABA. Few of these neurons were immunoreactive to tyrosine hydroxylase antibodies, which identify dopamine-containing neurons. Injections in the frontal and entorhinal cortices labeled many neurons near or within the dopaminergic A13 subdivision of the zona incerta. In addition, the incertocortical system was found to be significantly larger during early postnatal (2 to 3 weeks) development. The projection pattern of this newly discovered pathway resembles that of the monoaminergic and cholinergic systems, arising from the brainstem and forebrain, suggesting possible similarities of function.

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders.

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.

Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism.

The factors contributing to substantia nigra pars compacta (SNc) dopamine (DA) neuron death and striatal DA depletion in Parkinson's disease (PD) are still poorly understood. However, mitochondrial dysfunction, cellular energy depletion and oxidative stress appear to play important roles in the pathogenesis of PD. In view of this, the current study examined the potential of nicotinamide, a form of the B-complex vitamin niacin, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SNc cell loss and striatal DA depletion in two mouse MPTP models that respond differently to putative neuroprotective agents. Adult male C57Bl/6 mice received nicotinamide (125, 250 or 500 mg/kg i.p.) prior to either acute (four injections in 1 day at 2-h intervals) or sub-acute (two injections per day at 4-h intervals for 5 days) MPTP administration. Striatal DA levels, changes in numbers of tyrosine hydroxylase (TH)- and cresyl violet-stained cells in the SNc at 2 and 6 weeks following the last MPTP exposure were analyzed. Nicotinamide administration resulted in a dose-dependent sparing of striatal DA levels and SNc neurons in acute MPTP-treated animals. Only the highest dose of nicotinamide had similar effects in sub-acute MPTP-treated animals. At 6 weeks after MPTP exposure, there was some spontaneous recovery of striatal DA levels in both models: neuroprotective effects were still apparent in acute but not sub-acute MPTP-treated animals. These results show neuroprotective effects of nicotinamide in different mouse Parkinson models associated with different forms of cell death and suggest that nicotinamide may have broad neuroprotective potential in PD.

Postnatal lead exposure alters expression of forebrain p75 and TrkA nerve growth factor receptors.

Lead is a potent developmental neurotoxicant that affects many aspects of cognition and behavior. The hippocampus and striatum are among the areas particularly sensitive to the effects of lead and cholinergic neurons in both regions depend upon nerve growth factor (NGF) for their survival and maturation. The present study examined the extent to which postnatal lead exposure may affect the survival and expression of neuroptrophin receptors of septo-hippocampal cholinergic projection neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) and cholinergic neurons of the striatum. Weanling rats were fed chow containing lead acetate for 30 days and effects on cholinergic cell number and the number of cells expressing neurotrophin receptors p75(NGFR) and trkA were assessed. A decrease in the number of cells expressing p75(NGFR) and an increase in the number of cells expressing trkA receptor was observed in the MS/VDB of lead-exposed rats, without a loss of cholinergic cell number or alteration in cell size. Lead-exposure resulted in a significant decrease in trkA-expressing cells in the striatum but no change in the number or size of cholinergic neurons. These results suggest that a brief postnatal lead exposure does not result in loss of MS/VDB or striatal cholinergic neurons but does modify the expression of neurotrophin receptors in these regions. The significance of these effects on the septo-hippocampal and striatal functioning remains to be studied.

Sex-Related Abnormalities in Substantia Nigra Lipids in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder involving the selective loss of dopamine-producing neurons in the substantia nigra (SN). Differences in disease presentation, prevalence, and age of onset have been reported between males and females with PD. The content and composition of the major glycosphingolipids, phospholipids, and cholesterol were evaluated in the SN from 12 PD subjects and in 18 age-matched, neurologically normal controls. Total SN ganglioside sialic acid content and water content (%) were significantly lower in the male PD subjects than in the male controls. The content of all major gangliosides were reduced in the male PD subjects to some degree, but the neuronal-enriched gangliosides, GD1a and GT1b, were most significantly reduced. The distribution of phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol was also significantly lower in the male PD subjects than in the male controls. However, the distribution of myelin-enriched cerebrosides and sulfatides was significantly higher in the male PD subjects than in the male controls suggesting myelin sparing in the male PD subjects. No elevation was detected for astrocytosis-linked GD3. These neurochemical changes provide evidence of selective neuronal loss in SN of the males with PD without robust astrocytosis. In contrast to the SN lipid abnormalities found in the male PD subjects, no significant abnormalities were found in the female PD subjects for SN water content or for any major SN lipids. These data indicate sex-related differences in SN lipid abnormalities in PD.

Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure.

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner.

Behavioral persistence deficit in Parkinson's disease patients.

The present study was performed to examine the degree to which decreased task persistence may contribute to deficits in the ability of Parkinson's disease (PD) patients to perform a problem solving task. Patients with mild/moderate PD performed a computerized Tower of Hanoi task in which they planned and verbalized moves to solve the puzzle but did not need to produce a limb motor response. All patients were tested at least 14 h off medication. As expected from previous studies of planning abilities in PD, patients had significant problems performing this task and accuracy decreased specifically when patients were presented with the most difficult puzzles in the sequence. PD patients solved fewer of the most difficult puzzles than did control subjects, but also made significantly fewer attempts to solve those puzzles than controls. These results suggest that PD patients not only have planning and problem solving deficits as have been documented previously, but that at least part of this and perhaps other cognitive performance problems may result from difficulty in maintaining adequate mental effort to successfully complete difficult tasks.

Postnatal lead poisoning impairs behavioral recovery following brain damage.

Lead is a potent environmental toxicant with well-known effects on intelligence, school achievement and behavior. Lead exposure is also associated with an increased risk of a variety of health problems including cancer, hypertension, cardiovascular disease, and renal disease. Considering the risk of hypertension, cardiovascular problems, and stroke following lead exposure, the current research assessed the extent to which postnatal exposure to environmentally relevant levels of lead could impair the recovery from a later occurring brain injury. Using a photochemical thrombotic stroke model we found that postnatal lead exposure significantly impaired post-stroke recovery of beam walking ability and proprioceptive limb placing. Considering the increased risk for hypertension and cardiovascular disease in lead-exposed humans, diminished capacity for repair or adaptation following lead exposure needs to now be examined in greater detail.

Strain specific effects of low level lead exposure on associative learning and memory in rats.

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) rats. The present study examined the extent to which this differential effect of Pb on hippocampal gene expression might influence behavior. Animals (males and females) were tested in a trace fear conditioning paradigm to evaluate effects of Pb exposures (perinatal (PERI; gestation to postnatal day 21) or early postnatal (EPN; postnatal day 1 to day 21)) on associative learning and memory. All animals (Pb-exposed and non-Pb-exposed controls) showed normal acquisition of the conditioned stimulus (tone)-unconditioned stimulus (footshock) association. Long Evans rats showed a significant deficit in short- and long-term recall, influenced by sex and the timing of Pb exposure (PERI or EPN). In contrast, Pb exposure had no significant effect on memory consolidation or recall in any SD rats. These results further demonstrate the important influence of genetic background to the functional outcomes from developmental Pb exposure.

Developmental Lead and/or Prenatal Stress Exposures Followed by Different Types of Behavioral Experience Result in the Divergence of Brain Epigenetic Profiles in a Sex, Brain Region, and Time-Dependent Manner: Implications for Neurotoxicology.

Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb±PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb±PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a 'no behavioral experience' group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies.

Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood.

Developmental exposure to prenatal stress (PS) and lead (Pb) can affect brain development and adversely influence behavior and cognition. Epigenetic-based gene regulation is crucial for normal brain development and mis-regulation, in any form, can result in neurodevelopmental disorders. Post-translational histone modifications (PTHMs) are an integral and dynamic component of the epigenetic machinery involved in gene regulation. Exposures to Pb and/or PS may alter PTHM profiles, promoting lifelong alterations in brain function observed following Pb±PS exposure. Here we examined the effects of Pb±PS on global levels of activating marks H3K9Ac and H3K4Me3 and repressive marks H3K9Me2 and H3K27Me3 at different developmental stages: E18, PND0, PND6 and PND60. Dams were exposed to 0 or 100ppm Pb beginning 2 months prior to breeding followed by no PS (NS) or PS resulting in 4 offspring treatment groups per sex: 0-NS (control), 0-PS, 100-NS and 100-PS. Global levels of PTHMs varied from E18 through adulthood even in control mice, and were influenced by sex and brain-region. The developmental trajectory of these PTHM levels was further modified by Pb±PS in a sex-, brain region- and age-dependent manner. Females showed a preferential response to Pb alone in frontal cortex (FC) and differentially to PS alone and combined Pb+PS in hippocampus (HIPP). In males, PS-induced increases in PTHM levels in FC, whereas PS produced reductions in HIPP. Pb±PS-based changes in PTHM levels continued to be observed in adulthood (PND60), demonstrating the lasting effect of these early life environmental events on these histone marks. These results indicate that epigenetic consequences of Pb±PS and their contribution to mechanisms of toxicity are sex dependent. Additional studies will assist in understanding the functional significance of these changes in PTHM levels on expression of individual genes, functional pathways, and ultimately, their behavioral consequences.

Sensory and cognitive functions of the basal ganglia.

Recent studies have found that the basal ganglia are involved in diverse behavioral activities and suggest that they have executive functions. Highlights from the past year include anatomical and clinical studies that have used sophisticated, novel methods to confirm a role for the basal ganglia in somatosensory discrimination, visual perception, spatial working memory and habit learning.

The synthetic ceramide analog L-PDMP partially protects striatal dopamine levels but does not promote dopamine neuron survival in murine models of parkinsonism.

A number of previous studies have demonstrated a positive effect of exogenously administered monosialoganglioside GM1 on striatal dopamine (DA) levels and DA neuron survival in animal models of parkinsonism. However, due to low bioavailability of peripherally administered GM1, the present study investigated the neuroprotective/neurorestorative potential of enhancing endogenous GM1 biosynthesis by administration of the synthetic ceramide analog L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) in two mouse models of Parkinsonism produced by acute or subacute 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. L-PDMP treatment caused an increase in brain GM1 levels in both Parkinson models and resulted in a partial sparing of striatal DA levels in the subacute MPTP model but not in the acute MPTP model. L-PDMP treatment had no effect on DA neuron survival in either model. These data suggest that the administration of L-PDMP as a means to enhance endogenous brain GM1 levels may hold limited promise as a potential neuroprotective or neurorestorative therapeutic strategy for Parkinson's disease.

Effects of low level lead exposure on associative learning and memory in the rat: Influences of sex and developmental timing of exposure.

Lead (Pb) exposure during development impairs a variety of cognitive, behavioral and neurochemical processes resulting in deficits in learning, memory, attention, impulsivity and executive function. Numerous studies have attempted to model this effect of Pb in rodents, with the majority of studies focusing on hippocampus-associated spatial learning and memory processes. Using a different paradigm, trace fear conditioning, a process requiring coordinated integration of both the medial prefrontal cortex and the hippocampus, we have assessed the effects of Pb exposure on associative learning and memory. The present study examined both female and male long evans rats exposed to three environmentally relevant levels of Pb (150 ppm, 375 ppm and 750 ppm) during different developmental periods: perinatal (PERI; gestation-postnatal day 21), early postnatal (EPN; postnatal days 1-21) and late postnatal (LPN; postnatal days 1-55). Testing began at postnatal day 55 and consisted of a single day of acquisition training, and three post training time points (1, 2 and 10 days) to assess memory consolidation and recall. All animals, regardless of sex, developmental window or level of Pb-exposure, successfully acquired conditioned-unconditioned stimulus association during training. However, there were significant effects of Pb-exposure on consolidation and memory recall at days 1-10 post training. In females, EPN and LPN exposure to 150 ppm Pb (but not PERI exposure) significantly impaired recall. In contrast, only PERI 150 ppm and 750 ppm-exposed males had significant recall deficits. These data suggest a complex interaction between sex, developmental window of exposure and Pb-exposure level on consolidation and recall of associative memories.

Expression of striatal preprotachykinin mRNA in symptomatic and asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys is related to parkinsonian motor signs.

Striatal preprotachykinin (PPT) gene expression and [(3)H]mazindol binding were examined in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Some animals (n = 5) became moderately to severely parkinsonian after receiving large doses of MPTP over 9-30 d and remained symptomatic for a relatively short time (3 weeks to 3 months; acutely symptomatic group). A second group of animals (n = 5) received low doses of MPTP (1.5-12 months), developed cognitive impairments but displayed no gross motor deficits (asymptomatic group), and were killed 3-12 months after their final dose of MPTP. Other animals became moderately to severely parkinsonian after receiving escalating doses of MPTP (>6 months; n = 4) or high doses of MPTP (<1 month; n = 1) and remained symptomatic for 2.5-5.75 years (chronically symptomatic group). All MPTP-treated animals had extensive losses of [(3)H]mazindol binding in dorsal striatal sensorimotor regions with asymptomatic animals generally having a lesser degree of damage. However, PPT mRNA levels differed sharply among treatment groups. Symptomatic animals (acutely and chronically parkinsonian) had significantly decreased PPT mRNA levels in most striatal regions. In asymptomatic animals, PPT mRNA expression was not significantly different from that measured in control animals, despite decreases in [(3)H]mazindol binding in some striatal regions of similar magnitude to those observed in symptomatic animals. These observations suggest that PPT gene expression may be directly related to expression of parkinsonian motor symptomatology regardless of duration of MPTP exposure, duration of the parkinsonism, or extent of dopamine denervation. These results imply that the direct striatal output circuit may have a greater contribution to expression of parkinsonian symptomatology than proposed previously.