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Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats

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Abstract

We previously reported a loss of cholinergic neurons within the pedunculopontine tegmental nucleus (PPTg) in rats that had been intra-nigrally lesioned with the proteasomal inhibitor lactacystin, with levels of neuronal loss corresponding to that seen in the post-mortem pedunculopontine nucleus (PPN) of advanced Parkinson’s disease (PD) patients. Here we reveal lower expression values of the acetylcholine synthesising enzyme, choline acetyltransferase, within the remaining PPTg cholinergic neurons of lesioned rats compared to sham controls. We further characterise this animal model entailing dopaminergic- and non-dopaminergic neurodegeneration by reporting on stereological counts of non-cholinergic neurons, to determine whether the toxin is neuro-type specific. Cell counts between lesioned and sham-lesioned rats were analysed in terms of the topological distribution pattern across the rostro-caudal extent of the PPTg. The study also reports somatic hypotrophy in the remaining non-cholinergic neurons, particularly on the side closest to the nigral lesion. The cytotoxicity affecting the PPTg in this rat model of PD involves overexpression and accumulation of alpha-synuclein (αSYN), affecting cholinergic and non-cholinergic neurons as well as microglia on the lesioned hemispheric side. We ascertained that microglia within the PPTg become fully activated due to the extensive neuronal damage and neuronal death resulting from a lactacystin nigral lesion, displaying a distinct rostro-caudal distribution profile which correlates with PPTg neuronal loss, with the added implication that lactacystin-induced αSYN aggregation might trigger neuronophagia for promoting PPTg cell loss. The data provide critical insights into the mechanisms underlying the lactacystin rat model of PD, for studying the PPTg in health and when modelling neurodegenerative disease.

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Abbreviations

ACh:

Acetylcholine

αSYN:

Alpha-synuclein

ChAT:

Choline acetyltransferase

CR3:

Complement receptor type 3 receptor

CD11b:

Cluster of differentiation 11b

CV:

Coefficient of variation

CE:

Coefficient of error

CFV:

Cresyl fast violet

DBS:

Deep-brain stimulation

DAB:

3,3′-Diaminobenzidine

DPX:

Di-n-butyl-phthalate-xylene

DA:

Dopamine

EtOH:

Ethanol

GABA:

Gamma-aminobutyric acid

6-OHDA:

6-Hydroxydopamine

IHC:

Immunohistochemistry

ir:

Immunoreactive

i.p.:

Intraperitoneally

LDTg:

Laterodorsal tegmental nucleus

MFB:

Medial forebrain bundle

NeuN:

Neuronal-specific nuclear

NADPH:

Nicotinamide adenine dinucleotide phosphate

n/s:

Non-significant

NHS:

Normal horse serum

PD:

Parkinson’s disease

PPTg:

Pedunculopontine tegmental

PPN:

Pedunculopontine nucleus

PBS:

Phosphate buffered saline

PET:

Positron emission tomography

ROI:

Region of interest

RT:

Room temperature

SEM:

Standard error of the mean

SNpc:

Substantia nigra pars compacta

SNr:

Substantia nigra pars reticulata

TH:

Tyrosine hydroxylase

UPS:

Ubiquitin proteasomal system

VTA:

Ventral tegmental area

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Acknowledgments

This study received grant support from the British Pharmacological Society and the Rosetrees Trust, with both grants awarded to ISP.

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Authors and Affiliations

  1. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ, UK

    Joanna L. Elson

  2. Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa

    Joanna L. Elson

  3. School of Biomedical Sciences, Guy’s Campus, King’s College London, London, SE13QD, UK

    Abi Yates

  4. Division of Brain Sciences, Department of Medicine, Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, W12 ONN, UK

    Ilse S. Pienaar

  5. Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Ellison Place, Newcastle-upon-Tyne, NE1 8ST, UK

    Ilse S. Pienaar

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  1. Joanna L. Elson
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  2. Abi Yates
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  3. Ilse S. Pienaar
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Correspondence to Ilse S. Pienaar.

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Elson, J.L., Yates, A. & Pienaar, I.S. Pedunculopontine cell loss and protein aggregation direct microglia activation in parkinsonian rats. Brain Struct Funct 221, 2319–2341 (2016). https://doi.org/10.1007/s00429-015-1045-4

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  • DOI: https://doi.org/10.1007/s00429-015-1045-4

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