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

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, 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...

Metabolic, synaptic and behavioral impact of 5‐week chronic deep brain stimulation in hemiparkinsonian rats

“…), D2 receptor agonists or inhibition of endocannabinoid degradation (Kreitzer and Malenka ), while LTP by dopaminergic cells grafts (Rylander et al . ) or L‐DOPA administration (Picconi et al . ).…”

Striatal Plasticity in L-DOPA- and Graft-Induced Dyskinesia; The Common Link?

“…Even though transplanted neurons are able to innervate the host striatum, release DA, and reverse alterations in neuropeptide expression after a dopamine denervating lesion (Cenci et al, 1993 ) it is unclear whether they restore the synaptic network in the PD brain or if they cause further alterations in synaptic plasticity. The importance of this question lies in the fact that a functional integration from the grafted neurons into the host microcircuits with formation of bidirectional synaptic contacts between the host and grafted neurons would give superior therapeutic benefit than a mere neurochemical restoration (Rylander et al, 2013 ). Furthermore it will be of great relevance for novel cell therapies that are currently developing e.g., human embryonic stem cell derived neurons that have been shown to generate DA neurons with an authentic midbrain phenotype that survive transplantation and can restore motor deficits and synaptically be integrated from host neurons (Kriks et al, 2011 ; Grealish et al, 2014 ).…”

“…Previous extracellular electrophysiological recordings have shown that dopaminergic fetal neurons partially restore spontaneous neuronal firing in the striatum up to 2 mm from the core of the grafted area (Di Loreto et al, 1996 ; Stromberg et al, 2000 ) and also restore neuronal activity in the subthalamic nucleus (Rumpel et al, 2013 ). Yet only one study has explored the synaptic plasticity in striatal MSNs after fetal cell transplantation (Rylander et al, 2013 ). Here transplants of DA neurons were shown to partially restore activity-dependent LTP (see Figure 2D ) in contrast to 5-HT-rich transplants.…”

Optogenetics enables functional analysis of human embryonic stem cell–derived grafts in a Parkinson's disease model

“…+ APO versus HALO + 543 + APO, t = 4.81, P = 0.0002). Therefore, the apomorphine data also indicate that the presence of the graft, regardless of whether it is silenced or not, can rescue maladaptive behaviors thought to be associated with basal ganglia hypersensitivity 24,25 .…”