Elsevier

Neurobiology of Disease

Volume 32, Issue 2, November 2008, Pages 229-242
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2008.06.018Get rights and content

Abstract

Graft-induced dyskinesias (GIDs), side-effects found in clinical grafting trials for Parkinson's disease (PD), may be associated with the withdrawal of immunosuppression. The goal of this study was to determine the role of the immune response in GIDs. We examined levodopa-induced dyskinesias (LIDs), GID-like behaviors, and synaptic ultrastructure in levodopa-treated, grafted, parkinsonian rats with mild (sham), moderate (allografts) or high (allografts plus peripheral spleen cell injections) immune activation. Grafts attenuated amphetamine-induced rotations and LIDs, but two abnormal motor syndromes (tapping stereotypy, litter retrieval/chewing) emerged and increased with escalating immune activation. Immunohistochemical analyses confirmed immune activation and graft survival. Ultrastructural analyses showed increases in tyrosine hydroxylase-positive (TH+) axo-dendritic synapses, TH+ asymmetric specializations, and non-TH+ perforated synapses in grafted, compared to intact, striata. These features were exacerbated in rats with the highest immune activation and correlated statistically with GID-like behaviors, suggesting that immune-mediated aberrant synaptology may contribute to graft-induced aberrant behaviors.

Introduction

A major set-back to embryonic dopaminergic grafting trials in Parkinson's disease (PD) patients has been the development of troublesome post-graft abnormal involuntary movements in as many as 50% of trial participants (Hagell et al., 2002, Olanow et al., 2003). These so-called graft-induced dyskinesias (GIDs) have characteristics largely unique from common levodopa-induced dyskinesias (LIDs) and appear to more closely resemble biphasic drug-induced dyskinesias (Cenci and Hagell, 2005), often involving stereotypy and hyperkinesia and localized to either upper or lower extremities (Olanow et al., 2003, Hagell et al., 2002). This is in contrast to peak-dose LIDs, which are more widespread (involving both pair of extremities) and primarily dystonic and choreic (Fahn, 2000). Unlike peak-dose LIDs, GIDs are most commonly noted when plasma levodopa levels are low. An animal model of GIDs has recently been reported (Steece-Collier et al., 2003, Maries et al., 2006, Lane et al., 2006, Carlsson et al., 2006). While differences exist between clinical GIDs and the rat model, in both humans (Freed et al., 2001, Hagell et al., 2002, Olanow et al., 2003) and animals (Maries et al., 2006), grafting embryonic dopaminergic neurons into the parkinsonian striatum can result in the development of novel, aberrant motor behaviors at extended post-graft intervals.

Clinical observations suggest a link between the host immune system and GIDs. Specifically, GIDs were reported in patients that received no immunosuppression (Freed et al., 2001) or soon after the withdrawal of immunosuppression (Olanow et al., 2003, Hagell and Cenci, 2005). In two patients displaying GIDs, post-mortem examination showed that the surviving grafts were surrounded by activated microglia (Olanow et al., 2003). This coincidence of GID development and immunosuppression withdrawal suggests that the host immune response contributes to the development of these behaviors following dopaminergic grafting in the parkinsonian brain; however, this hypothesis remains to be tested.

An immune-mediated alteration in synapses is a possible explanation for the emergence of GIDs (e.g.: Tonelli et al., 2005). Indeed, synaptic remodeling is a key feature of neuroleptic-induced dyskinesias (Meredith et al., 2000), indicating a direct link between synaptic structural changes and dyskinesias. The dendrites of medium spiny neurons (MSNs) are densely covered with spines, which are the primary targets of afferent, cortical glutamatergic and nigral dopaminergic neurons (Bolam, 1984, Freund et al., 1984). There is evidence from earlier studies that striatal dopaminergic grafts that reinnervate the host form aberrant connections with these MSNs (Freund et al., 1985, Mahalik et al., 1985, Clarke et al., 1988, Leranth et al., 1998). However, none of these studies examined the potential importance of these or other synaptic changes in the graft–host relationship over time, or in the emergence of abnormal behaviors.

We examined varying levels of immune activation on striatal synaptic organization in a well characterized rat allograft model (Duan et al., 1995a, Duan et al., 1995b, Duan et al., 1997), as the first step in understanding whether immune cells impact the ultrastructural characteristics of new synapses from grafts or existing host terminals. We then correlated changes in the synaptic organization with GIDs in these rats.

Section snippets

Animals

Adult male Sprague Dawley rats (225–250 g at the start of the study) were kept on a 12-hour light–dark cycle with ad libitum food and water. The rats were housed and treated according to the rules and regulations of NIH and Institutional Guidelines on the Care and Use of Animals. To correlate host immune response severity with the severity and frequency of dyskinesias, rats were placed into 1 of 3 groups of varying immune status: 1) minimal immune response (sham-grafted rats; n = 16), 2) moderate

Amphetamine-induced rotational behavior

Rats were observed 2 weeks following 6-OHDA and again on weeks 9, 16 and 20 post-grafting to determine lesion success and post-graft behavioral recovery. Two weeks post-lesion (pre-graft), rats in all groups showed a similar severity in amphetamine-induced contralateral turns per 90 min (F2,30 = 0.62, p = 0.55; Sham: 852.88 ± 87.47; Allograft: 714.50 ± 67.85; G21 Allograft + spleen: 841.33 ± 88.90). However, by week 9 post-grafting, all dopamine-grafted groups showed significant improvements compared to

Discussion

This study is the first to demonstrate that aberrant synaptic features in the parkinsonian striatum of rats following dopaminergic cell grafting are associated with the expression of graft-mediated motor dysfunction. While abnormalities in the synaptic connections of grafted dopaminergic neurons have previously been documented (e.g. Freund et al., 1985, Mahalik et al., 1985, Leranth et al., 1998), the biological contributors to this reorganization and behavioral consequences remain obscure. We

Acknowledgments

The authors would like to thank Dr. Wei-Ming Duan of Louisiana State University, for his valuable suggestions regarding spleen cell injections. We would also like to thank the statisticians at Rush University, in particular Dr. Sue Leurgans, for their guidance with our data analyses. Further, we would like to acknowledge the outstanding technical assistance of Nathan Levine, Jennifer Stancati and Brian Daley, and the support of the Electron Microscopy Center at Rosalind Franklin University.

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