The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors

Soderstrom, Katherine E.; Meredith, Gloria E.; Freeman, Thomas B.; McGuire, Susan O.; Collier, Timothy J.; Sortwell, Caryl E.; Wu, Qun; Steece‐Collier, Kathy

doi:10.1016/j.nbd.2008.06.018

Cited by 61 publications

(85 citation statements)

References 54 publications

(93 reference statements)

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“…Our result of an absent LTD in the DL striatum points to functional differences between a graft-derived dopaminergic innervation and the residual endogenous DA transmission that persists after a partial lesion (12). Indeed, it has been demonstrated that striatal dopaminergic grafts that reinnervate striatum form aberrant connections with the host MSNs, which are associated with the development of graft-induced dyskinesia (52).…”

Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 73%

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Rylander

Bagetta

Pendolino

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine-and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamineenriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.onpharmacological dopamine (DA) replacement approaches to the therapy of Parkinson disease (PD) focus on the transplantation of DA-producing neurons into the striatum. Parkinson disease is indeed viewed as the disease of choice to develop intracerebral transplantation therapies, and promising results have been obtained both in experimental models and in some patients using embryonic DA neurons (1, 2). Embryonic DA neurons are able to innervate the host striatum, release DA, and reverse alterations in neuropeptide expression after a parkinsonian lesion (3). There is a continuous debate about whether these effects are sufficient for transplanted neurons to partially restore clinical symptoms or whether other underlying mechanisms also are required. In particular, a functional integration of the graft into the host microcircuits, with bidirectional synaptic contacts between the host and grafted neurons, may give superior therapeutic benefit than a mere neurochemical restoration. Transplanted DA neurons are able to form synapses with the surrounding striatal medium-sized spiny neurons (MSNs) (4) and receive innervation from the host neurons with bidirectional synaptic interactions (5-7). It is, however, unknown wh...

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Section: Da Grafted Neurons Can Therapeutically Restore Plasticity Inmentioning

confidence: 73%

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Rylander

Bagetta

Pendolino

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Dyskinesias, or specifically LID, are an often debilitating side-effect of DA replacement therapy that can significantly compromise quality of life for persons with PD [19]. Pretreatment with levodopa and the establishment of LID was done: 1) to emulate the status of all PD patients that have thus far received a DA neuron graft, and 2) because this complex behavioral malady can be ameliorated by DA neuron grafts in parkinsonian rats [5,11,20–22] and patients (for review [23]). Overall, the Collier et al study [8] showed that while LID behavior was ameliorated in all DA grafted rats, the young rats with the fewest number of surviving grafted DA neurons and least amount of graft-derived neurite outgrowth, showed the fastest rate and greatest magnitude of behavioral recovery.…”

Section: Identifying Potential Risk Factors For Cell Replacement Stramentioning

confidence: 99%

“…Yet, the impact of the environment of the aged brain on the response to cell therapy has received limited attention in laboratory studies and only now is being inferred from outcomes associated with PD patients transplanted many years previously. Decades of preclinical and clinical research on DA neuron grafting in PD have suggested three primary risk factors that are associated with graft failure: 1) advanced age of the host [8,2,9,10]; 2) extensive striatal DA denervation [1,4,5,11]; and most recently 3) alpha-synuclein (α-syn) pathology [12–16]. Arguably, all of these factors can be associated with the environment of the aging brain.…”

Section: Introductionmentioning

confidence: 99%

Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic

Mercado

Collier

Freeman

et al. 2016

J Clin Cell Immunol

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The primary risk factor associated with Parkinson's disease (PD) is advanced age. While there are symptomatic therapies for PD, efficacy of these eventually wane and/or side-effects develop over time. An alternative experimental therapy that has received a great deal of attention over the past several decades has been neural transplantation aimed at replacing nigral dopamine (DA) neurons that degenerate in PD. However, in PD patients and parkinsonian rats, advanced age is associated with inferior benefit following intrastriatal grafting of embryonic DA neurons. Traditionally it has been thought that decreased therapeutic benefit results from the decreased survival of grafted DA neurons and the accompanying poor reinnervation observed in the aged host. However, recent clinical and preclinical data suggest that factors inherent to the aged striatum per se limit successful brain repair. In this short communication, we focus discussion on the implications of our recent grafting study in aged parkinsonian rats, with additional emphasis on a recent clinical report of the outcome of cell therapy in an aged PD patient with long-term (24 years) survival of DA neuron grafts. To address aging as a limiting factor in successful brain repair, we use the example of cell transplantation as a means to interrogate the environment of the aged striatum and identify factors that may, or may not, respond to interventions aimed at improving the prospects for adequate repair of the aged brain. We offer discussion of how these recent reports, in the context of other historical grafting studies, might provide new insight into specific risk factors that have potential to negatively impact all DA cell or terminal replacement strategies for clinical use in PD.

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“…Multiple implantation sites including caudate nucleus and globus pallidus can improve anti-parkinsonian efficacy as well as address the issue that PD involves more than nigrostriatal DA loss (3)(4)(5)36). Development of models of dyskinesias in rodents (103) and monkeys (91) are helping researchers understand the nature of runaway dyskinesias, primarily what characteristics of the graft and host response affect the efficacy of the transplant and possible subsequent development of the abnormal movements (29,30,144). The prediction of clinical results from preclinical studies depends on using experimental designs that allow blind data acquisition and statistical analysis, assessing the therapy in investigational conditions that parallel clinical situations, looking for potential sources of complications or side effects and limiting optimism bias when reporting outcomes.…”

Section: The Role Of Preclinical Studies In the Application Of Past Amentioning

confidence: 99%

Cell-Based Therapies for Parkinson's Disease: Past, Present, and Future

Fitzpatrick¹,

Raschke²,

Emborg

2009

Antioxidants & Redox Signaling

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Parkinson's disease (PD) researchers have pioneered the use of cell-based therapies (CBTs) in the central nervous system. CBTs for PD were originally envisioned as a way to replace the dopaminergic nigral neurons lost with the disease. Several sources of catecholaminergic cells, including autografts of adrenal medulla and allografts or xenografts of mesencephalic fetal tissue, were successfully assessed in animal models, but their clinical translation has yielded poor results and much controversy. Recent breakthroughs on cell biology are helping to develop novel cell lines that could be used for regenerative medicine. Their future successful clinical application depends on identifying and solving the problems encountered in previous CBTs trials. In this review, we critically analyze past CBTs' clinical translation, the impact of the host in graft survival, and the role of preclinical studies and emerging new cell lines. We propose that the prediction of clinical results from preclinical studies requires experimental designs that allow blind data acquisition and statistical analysis, assessment of the therapy in models that parallel clinical conditions, looking for sources of complications or side effects, and limiting optimism bias when reporting outcomes.

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The synaptic impact of the host immune response in a parkinsonian allograft rat model: Influence on graft-derived aberrant behaviors

Cited by 61 publications

References 54 publications

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic

Cell-Based Therapies for Parkinson's Disease: Past, Present, and Future

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