Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Bárbara Mendes-Pinheiro,Carina Soares-Cunha,António José Salgado,Sara Duarte-Silva,Jonas Campos,Daniela Monteiro-Fernandes,Ana Marote,Diogo Santos,Eduardo Loureiro-Campos,Sandra Barata-Antunes,Luísa Pinto

doi:10.3390/ijms222111530

Bárbara Mendes-Pinheiro, Carina Soares-Cunha + Show 9 more

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https://doi.org/10.3390/ijms222111530

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Abstract

Parkinson’s disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson’s disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry’s degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.

Highlights

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder, affecting around six million people worldwide [1]
Animals were trained in the square beam (12 mm), and on the day of the test, two more beams with a higher level of difficulty were presented to the animals. 6-OHDA-lesioned animals had a worse performance in all beams, after 3 and 11 weeks post-lesion when compared to the control group
The results showed that 6-OHDA-lesioned animals predominantly use the paw ipsilateral to the lesion in exploration of the cylinder walls, compared to the vehicle group (Figure 1d)

Summary

Introduction

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder, affecting around six million people worldwide [1] Motor symptoms, such as bradykinesia, rest tremor and rigidity, are the core of PD clinical features that develop due to the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) [2]. This neuronal loss is accompanied by the presence of cytoplasmatic inclusions or Lewy bodies (LBs), mainly composed of α-synuclein protein, that possibly propagates between synaptically-connected areas in a prion-like manner [3]. Efforts have been made to develop alternative therapeutical approaches, and for that, the use of PD pre-clinical models is a critical step to test new disease-modifying strategies

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