Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

Abstract

Progressive degeneration of dopaminergic neurons in the substantia nigra (SN) is the underlying cause of Parkinson’s disease (PD). The disease in early stages is difficult to diagnose, because behavioral deficits are masked by compensatory processes. Astrocytic and microglial pathology precedes motor symptoms. Besides supportive functions of astrocytes in the brain, their role in PD is unrecognized. Prolonged dysfunction of astrocytes could increase the vulnerability of dopaminergic neurons and advance their degeneration during aging. The aim of our studies was to find out whether prolonged dysfunction of astrocytes in the SN is deleterious for neuronal functioning and if it influences their survival after toxic insult or changes the compensatory potential of the remaining neurons. In Wistar rat model, we induced activation, prolonged dysfunction, and death of astrocytes by chronic infusion of fluorocitrate (FC) into the SN, without causing dopaminergic neuron degeneration. Strongly enhanced dopamine turnover in the SN after 7 days of FC infusion was induced probably by microglia activated in response to astrocyte stress. The FC effect was reversible, and astrocyte pool was replenished 3 weeks after the end of infusion. Importantly, the prolonged astrocyte dysfunction and microglia activation accelerated degeneration of dopaminergic neurons induced by 6-hydroxydopamine and blocked the behavioral compensation normally observed after moderate neurodegeneration. Impaired astrocyte functioning, activation of microglia, diminishing compensatory capability of the dopaminergic system, and increasing neuronal vulnerability to external insults could be the underlying causes of PD. This animal model of prolonged astrocyte dysfunction can be useful for in vivo studies of glia–microglia–neuron interaction.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-017-0529-z) contains supplementary material, which is available to authorized users.

Boosting Antioxidant Self-defenses by Grafting Astrocytes Rejuvenates the Aged Microenvironment and Mitigates Nigrostriatal Toxicity in Parkinsonian Brain via an Nrf2-Driven Wnt/β-Catenin Prosurvival Axis

“…In light of the emerging implications of dysfunctional As in major human NDs (Endo et al, 2015;Anderson et al, 2016;L'Episcopo et al, 2016L'Episcopo et al, , 2018aBooth et al, 2017;Patel et al, 2019), together with the critical role of As and As-derived factors in both pharmacological and cell therapeutical interventions (Kondo et al, 2014;Yang et al, 2014;Nicaise et al, 2015;Hall et al, 2017;Rivetti di Val Cervo et al, 2017;Barker et al, 2018;Du et al, 2018;Kuter et al, 2018;Song et al, 2018;Bali et al, 2019;Klapper et al, 2019;Rizor et al, 2019), our findings highlight As-focused therapies as the crucial key for beneficial outcomes in PD.…”

“…Conversely, As-secreted antioxidant factors represent a critical self-protective system against MPTP and 6-OHDA cytotoxicity (Chen et al, 2009). In fact, the prolonged dysfunction of As and activation of microglia accelerate degeneration of DAergic neurons in the rat SN and block compensation of early motor dysfunction induced by 6-OHDA (Kuter et al, 2018).…”

Astrocyte support is important for the compensatory potential of the nigrostriatal system neurons during early neurodegeneration

“…Stereotaxic brain operations were performed as described in Kuter et al. ( ) under ketamine and xylasine anesthesia (Biowet, Puławy, Poland) with desipramine (Sigma‐Aldrich, Munich, Germany) to protect the noradrenergic terminals. To induce degeneration of dopaminergic neurons the animals were stereotaxically, bilaterally injected with 6‐OHDA HBr (3 μg base/3 μL per side; Sigma‐Aldrich) into the passing fibers of the medial forebrain bundle (MFB), at coordinates: AP: 1.4 mm, L: ±1.6 mm, V: 8.7 mm from bregma (Paxinos and Watson ).…”

“…Our previous research (Kuter et al . ) documented that prolonged infusion of astrocytic toxin fluorocitrate (FC) into the SN caused death of approx. 30% of astrocytes (decreased S100+ cell density and expression of ALDH1L1), activation of remaining alive astrocytes (increased Glial Fibrillary Acidic Protein (GFAP) expression, changes in morphology) and concomitant activation of microglia, while sparing neurons.…”

Astrocytic atrophy as a pathological feature of Parkinson’s disease with LRRK2 mutation

“…Furthermore, astrocytes from substantia nigra seem to be unusually vulnerable to ischemic attack [51] and oxidative stress [52]. Loss of astroglial support may act as an exacerbating factor in neurodegenerative process; chronically malfunctional astroglia was suggested to contribute to death of dopaminergic neurones [53]. It is early to conclude that astrocytic atrophy is the hallmark of PD until the same astrocytic atrophy is characterised in situ in patient's brain tissues or in astrocytes derived from other mutations.…”