| Abstract: | ![]()
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. |
