Motor learning and metaplasticity in striatal neurons: relevance for Parkinson’s disease

Abstract

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

“…Similar results were observed that human α-syn (h-α-syn) overexpression caused signi cant loss of dopaminergic neurons in the SNc (Fig. 7c) [52], reduction of TH and DAT protein levels in the SNc (Fig. 7d) and STR ( Supplementary Fig.17c), and these changes were markedly rescued by celastrol administration.…”

“…Recombinant AAVs (serotype 2 genome packaged in serotype 9 capsid) were used for the expression of human wild-type α-syn, GFP driven by the human synapsin-1 promoter and enhanced using a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) [51,52].…”

Contributions of the basal ganglia to action sequence learning and performance

“…Notably, however, mice were very slow to acquire lever pressing for D2 stimulation, the frequency of lever pressing was very low, and these mice pressed the laserpaired lever just as often as the inactive lever. A more recent study showed that D1 but not D2 receptors in the DLS mediate LTP during early rotarod learning in mice (Giordano et al, 2018).…”

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis

“…These findings led to the hypothesis that local cholinergic neurons could be substituting for extrinsic glutamate following cortical ablations . Current work has explored similar ideas and the local plasticity of MSN firing has been found to be much greater than previously thought in the brain slice preparation from typical tissue as well as after alteration in brain connectivity or physiology (Giordano et al, 2018). Furthermore, recent work has pinpointed significant contributions of acetylcholine interneurons influencing thalamostriatal activity and found applications to better understand the neuropathology of Parkinson's disease (Li & Dauer, 2019;Tanimura, Du, Kondapalli, Wokosin, & Surmeier, 2019).…”