Our laboratory has previously demonstrated that viral administration of glial cell line-derived neurotrophic factor (AdGDNF), one week prior to a controlled cortical impact (CCI) over the forelimb sensorimotor cortex of the rat (FL-SMC) is neuroprotective, but does not significantly enhance recovery of sensorimotor function. One possible explanation for this discrepancy is that although protected, neurons may not have been functional due to enduring metabolic deficiencies. Additionally, metabolic events following TBI may interfere with expression of therapeutic proteins administered to the injured brain via gene therapy. The current study focused on enhancing the metabolic function of the brain by increasing cerebral blood flow (CBF) with l-arginine in conjunction with administration of AdGDNF immediately following CCI. An adenoviral vector harboring human GDNF was injected unilaterally into FL-SMC of the rat immediately following a unilateral CCI over the FL-SMC. Within 30min of the CCI and AdGDNF injections, some animals were injected with l-arginine (i.v.). Tests of forelimb function and asymmetry were administered for 4weeks post-injury. Animals were sacrificed and contusion size and GDNF protein expression measured. This study demonstrated that rats treated with AdGDNF and l-arginine post-CCI had a significantly smaller contusion than injured rats who did not receive any treatment, or injured rats treated with either AdGDNF or l-arginine alone. Nevertheless, no amelioration of behavioral deficits was seen. These findings suggest that AdGDNF alone following a CCI was not therapeutic and although combining it with l-arginine decreased contusion size, it did not enhance behavioral recovery.

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.

Jeffrey A. Klein Franklin University, North Chicago, IL, USA ‡Department of Neurosurgery, University of South Florida, Tampa, Department of Neuroscience, University of Florida, Gainesville, FL, USA FL, USA §Department of Pathology, Loyola University Medical School, Loyola University Chicago, Maywood, IL, USA Recovery from brain injury can be thought of as a relearning proDepartment of Neurology, University of Cincinnati, Cincinnati, cess whereby spared neural tissue is retrained to compensate for lost or impaired functions. The neural mechanisms underlying recovery OH, USA appear to involve reorganization of remaining neural circuitry through changes in synaptic connectivity within residual neural tissue. ThereGraft-induced dyskinesias (GIDs) have been reported in Parkinfore, manipulations that promote synaptic plasticity may enhance exson’s disease patients transplanted with fetal dopamine neurons folperience-dependent recovery of function after brain injury. We have lowing the withdrawal of immunosuppression (Olanow, 2003; Hagell developed a rodent model of cortical ischemia to test the viability of & Cenci, 2005; Piccini, 2005). However, definitive association of imsuch treatments. The model involves training rats to criterion on a mune activation with GIDs and the mechanisms involved remain to skilled forelimb reaching task prior to induced focal ischemic infarcts be elucidated. Synaptic remodeling is a key feature of haloperidolvia either electrocoagulation or chemical vasoconstriction of the midinduced dyskinesias (Meredith, 2000), suggesting its role in the develdle cerebral artery. The animals are then given daily motor rehabilitaopment of aberrant behaviors. To determine if enhanced host immune tion on the same skilled reaching task. Intracortical microstimulation response and immune-mediated synaptic reorganization are associated is used to assess the topography of movement representations within with GIDs, dyskinesia profiles and synaptic ultrastructure of grafted, residual cortex. Using this model we show that direct electrical stimuparkinsonian rats with mild (sham grafts), moderate (allografts), or lation of motor cortex significantly improves performance on a skilled high (allografts plus peripheral spleen cell injections) immune activareaching task. The enhanced recovery is also associated with signifition were compared. Following grafting, rats received daily injections cantly greater motor map expansion and reorganization in residual corof levodopa and were observed for levodopa-induced dyskinesias tex. The same model demonstrates that stochastic electrical stimulation (LIDs) and GIDs. Grafting resulted in an attenuation of LIDs, and the of peripheral sensory afferents also induces enhanced motor recovery emergence of two novel types of abnormal involuntary movements, a and motor map reorganization. Finally, administration of two different compulsive tapping stereotypy employing the forepaw contralateral to type IV phosphodiesterase inhibitors known to upregulate the cAMP/ the graft (tapping dyskinesia; TPD), and a compulsive goal-directed CREB pathway significantly enhanced motor recovery and motor map grabbing and/or chewing of litter (facial forelimb dyskinesia; FFD). reorganization. The relationship between the amount of motor recovBoth of these novel behaviors were absent in sham-grafted rats, and ery and motor map reorganization in all three treatment interventions elevated in allografted rats. Tapping dyskinesia was further exaceris also not linear. The results suggest that there may be a critical bated in allografted rats receiving a secondary immune challenge. For amount of cortical reorganization induced by adjuvant treatments that ultrastructural analysis, allografted rats were sacrificed at 10 and 21 is required before motor recovery is significantly increased above that weeks postgrafting. Analysis showed features of aberrant synaptic observed with standard rehabilitation. connectivity in allografted rats, many of which were exacerbated in rats with the highest degree of immune activation. Altered synaptic features of tyrosine hydroxylase-positive (TH+) and asymmetrical, presumably glutamatergic, synapses significantly correlated with many The Impact of the Host Immune Response on Graft-Derived of the GIDs observed. These findings suggest that the host immune Synapses in the Allografted Rat: Influence on Dyskinesias response modulates GIDs through enhancing aberrant synaptic reorganization in the grafted parkinsonian rat. K. E. Soderstrom,* G. Meredith,† T. B. Freeman,‡ S. O. McGuire,§ T. J. Collier, C. E. Sortwell, and K. Steece-Collier