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BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

ABSTRACT: High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn-exposed non-human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn-exposure-related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.

SUBMITTER: Stansfield KH

PROVIDER: S-EPMC4296578 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

Stansfield Kirstie H KH Bichell Terry Jo TJ Bowman Aaron B AB Guilarte Tomás R TR

Journal of neurochemistry 20140902 5

High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a ...[more]

PMID: 25099302

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Project description:Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.

Project description:The classical motor symptoms of Parkinson's disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days. In order to assess the consequences of dopamine depletion, mice were analyzed 21 days after the last injection. In order to test reversibility of MSN changes we exploited the property of this model that striatal axon terminals regenerate by sprouting within 90 days and analyzed a second cohort 90 days after MPTP. Degeneration of dopaminergic neurons was confirmed by counting TH-positive neurons in the substantia nigra and by analyzing striatal catecholamines. Striatal catecholamine recovered 90 days after MPTP. MSN morphology was visualized by Golgi staining and quantified as total dendritic length, number of dendritic branch points, and density of dendritic spines. All morphological parameters of striatal MSN were reduced 21 days after MPTP. Statistical analysis indicated that dendritic pruning and the reduction of spine density represent two distinct responses to dopamine depletion. Ninety days after MPTP, all morphological changes recovered. Our findings demonstrate that morphological changes in striatal MSN resulting from dopamine depletion are reversible. They suggest that under optimal conditions, symptomatic dopaminergic therapy might be able to prevent maladaptive plasticity and long-term motor complications in PD patients.

Dataset Information

BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

Publications

BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

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