Dopaminergic modulation of short-term synaptic plasticity at striatal inhibitory synapses

Circuit properties, such as the selection of motor synergies, have been posited as relevant tasks for the recurrent inhibitory synapses between spiny projection neurons of the neostriatum, a nucleus of the basal ganglia participating in procedural learning and voluntary motor control. Here we show how the dopaminergic system regulates short-term plasticity (STP) in these synapses. STP is thought to endow neuronal circuits with computational powers such as gain control, filtering, and the emergence of transitory net states. But little is known about STP regulation. Employing unitary and population synaptic recordings, we observed that activation of dopamine receptors can modulate STP between spiny neurons. A D(1)-class agonist enhances, whereas a D(2)-class agonist decreases, short-term depression most probably by synaptic redistribution. Presynaptic receptors appear to be responsible for this modulation. In contrast, STP between fast-spiking interneurons and spiny projection neurons is largely unregulated despite expressing presynaptic receptors. Thus, the present experiments provide an explanation for dopamine actions at the circuit level: the control of STP between lateral connections of output neurons and the reorganization of the balance between different forms of inhibitory transmission. Theoretically, D(1) receptors would promote a sensitive, responsive state for temporal precision (dynamic component), whereas D(2) receptors would sense background activity (static component).     

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

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, dopamine-enriched 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.Nonpharmacological 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 whether these plastic changes are sufficient to restore the basic functional properties of the host neurons essential for corticostriatal control of movements (8). This study attempts to understand whether neural transplants have the ability to restore activity-dependent synaptic plasticity in the host corticostriatal pathway.We have herein investigated corticostriatal plasticity after transplantation of DA and 5-HT neurons in host MSNs in an experimental model of PD. Dopamine is critical for inducing long-term striatal plasticity, i.e., long-term potentiation (LTP) and long-term depression (LTD) in MSNs (9). The changes are mediated by the activation of ionotropic glutamate receptors, i.e., alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, as well as by the activation of DA receptors. Consequently, animal models of severe DA denervation have demonstrated a loss of both forms of corticostriatal plasticity in the dorsolateral (DL) striatum (10, 11). A partial DA denervation, on the other hand, spares LTD in the DL striatum (12). Also clinical studies have revealed an impairment of synaptic plasticity in the corticostriatal pathway (13).Using an experimental model of PD, we here demonstrate that transplanted DA neurons are efficient in restoring corticostriatal plasticity in the densely innervated area close to the graft whereas more sparsely innervated areas remain unaffected. This restoration is in contrast to the effect of transplanted 5-HT neurons that were unable to restore any type of plasticity.     

Recipient-derived hepatocytes in liver transplants: a rare event in sex-mismatched transplants

Bone marrow-derived stem cells have been shown to engraft and populate native tissues during repair and in transplanted animal tissues. Very few studies have been performed in humans to evaluate the possibility of stem cell engraftment in transplanted tissues. In human renal transplants, recipient cells have been demonstrated within vascular and interstitial structures. In a previous study of patients with hepatic transplants, hepatocytes with XY chromosome patterns have been detected in sex-mismatched female to male transplanted livers in a small number of cases. Because of the possibility of Y chromosome microchimerism of females with male offspring, we analyzed the presence of X and Y chromosomes in liver biopsies of 13 patients with sex-mismatched liver transplants (8 female to male, 5 male to female) and long transplant to biopsy intervals (1.2 to 12 years; mean, 4.5 years). We were able to detect recipient-specific sex chromosomal patterns in inflammatory cells by fluorescent in situ hybridization/immunohistochemistry combination within the liver parenchyma but not within hepatocytes. In conclusion, recipient engraftment of stem cells may be an early feature in liver transplant but may be an infrequent persistent feature in long-term grafts.     

Associative long-term potentiation in hippocampal slices.

Interactions between two excitatory monosynaptic inputs to hippocampal neurons of the CA1 region were examined in the in vitro slice. By adjusting the strengths of the electrical stimuli delivered to the two input pathways, one was made to generate a weak and the other a strong synaptic response. Simultaneous tetanic stimulation of both input pathways resulted in a subsequent long-term enhanced synaptic efficacy in the weak input under conditions in which the same tetanic stimulation of either input alone failed to have this effect. This form of long-term synaptic potentiation (LTP), known as associative LTP, was shown in some cases to last hours without decrement. The plastic changes were localized within the CA1 region and appear to reside in the pre- or postsynaptic elements of the monosynaptic excitatory input to the pyramidal neurons. The increased synaptic efficacy could not be accounted for by any of several measured postsynaptic passive membrane properties.     

Legionella infections in cyclosporine-immunosuppressed cardiac transplants

Pulmonary infections from bacterial or viral agents, as well as rare infectious agents, such as Toxoplasma gondii, Aspergillus, and Pneumocystis carinii, have been a bane to the clinician in charge of the care of transplant patients. One such opportunistic Organism, Legionella pneumophila, was responsible for four episodes of infection in three of our patients who survived due to better management of immunosuppression, together with aggressive therapy and early diagnosis of the infectious complications.     

Infections in recipients of kidney transplants

A review of infections in kidney transplant recipients is presented in this article, beginning with a discussion of the pretransplant infectious diseases evaluation and an overview of the timing of infectious posttransplant, and then focusing on individual types of infection.     

Late changes in aorto-renal vein transplants

The results of 152 renal artery reconstructions in 128 hypertensive patients were reviewed 1 to 15 years postoperatively in 89 of 98 survivors. Forty-seven (52.8%) patients were normotensive, 29 (32.6%) are improved, and 13 (14.6%) were not improved. Angiography was performed 1 to 11 years after the operation. Only 2 of the 31 vein implants showed an adequate lumen. Four vein grafts were occluded. In 2 out of 4 stenosed transplants stenosis was functionally significant, and the patients with recurrent hypertension underwent re-reconstruction. The causes of the stenoses were severe constriction by scar tissue and extensive subintimal cellular proliferation of the vein graft. Twelve of 31 vein bypass grafts were dilated by an average of 22%. The average increase in caliber of the remaining 9 vein grafts was 106%. The possible contributory factors were forceful distension, excessive adventitial dissection, inadequate storage of the vein, ischemic damage of the vein wall (especially in younger patients), and the increase flow rate through the transplant.     

Cytomegalovirus vaccine in renal transplants.

The frequency of solid tumors was evaluated in 628 consecutive patients with multiple myeloma who had been treated with various melphalan-prednisone combinations. Among those patients who lived at least 2 months, the incidence and diversity of second tumors were similar to those in normal persons of the same age and duration at risk. The diagnosis was usually made within 2 years after the start of chemotherapy for the myeloma. Long-term melphalan therapy did not seem to contribute to the pathogenesis of second solid tumors in patients with multiple myeloma.     

Vascular anastomosis techniques in renal transplants

In our series of 250 RT's 192 (76.8%) from living donors and 58 (23.27%) from cadaver donors, there were 207 (88.8%) kidneys with a single renal artery, 40 (16%) with a double artery and 3 (1.2%) with a triple artery. End to side anastomosis to common iliac vessels was the most frequently used technique for kidneys with a single renal artery (52%). Extracorporeal renal surgery was performed on 83.7% of kidneys with multiple arteries. There were 32 (12.8%) complications with 6 (2.4%) unsuccessful RT's due to technical reasons. The actuarial survival of patients and grafts after 5 years from live donors was 87% and 69% and from cadaver donors was 78% and 46%, respectively.     

Human fetal pancreas transplants

Human fetal pancreatic islet tissue has several advantages as a transplant source for the amelioration of insulin deficiency in patients with Type I diabetes mellitus. It is now possible to obtain viable tissue, store and ship the tissue without adverse effects on the insulin secretory capacity, and transplant either minced tissue or isolated islet-like cell clusters following digestion and culture into animal models or man. A number of centers have undertaken studies of human fetal pancreatic allografts in man. Optimal results have occurred when pooled tissue from six to 20 donors has been implanted and a number of sites have been studied. The authors' own experience in four recipients who did not receive immunosuppression has documented insulin secretion for up to 1 year in the absence of an anticytoplasmic islet cell antibody response on the part of the recipients. Nevertheless, the procedure has not resulted in insulin independence for the recipients and the implanted tissue has not secreted insulin in response to a glucose-amino acid challenge in a normal physiologic pattern. Thus, human fetal pancreatic transplantation for the treatment of Type I diabetes remains an experimental approach.     

Umbilical cord blood transplants

With the establishment of cord blood banks, the number of related and unrelated umbilical cord blood transplants is increasing worldwide. Close links have been established with the cord blood banks. Available data showed that umbilical cord blood transplants offer overall results comparable to those obtained with related or unrelated bone marrow transplants. Several differences were found: engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications, and the incidence of acute and chronic graft-versus-host disease was significantly reduced with cord blood grafts, even in HLA-mismatched transplants and in adults. In patients with leukemia, the rate of relapse appeared to be similar to that documented in bone marrow transplant recipients. These data confirm the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.