A correct interplay between dopamine (DA) and glutamate is essential for corticostriatal synaptic plasticity and motor activity. In an experimental model of Parkinson's disease (PD) obtained in rats, the complete depletion of striatal DA, mimicking advanced stages of the disease, results in the loss of both forms of striatal plasticity: long-term potentiation (LTP) and long-term depression (LTD). However, early PD stages are characterized by an incomplete reduction in striatal DA levels. The mechanism by which this incomplete reduction in DA level affects striatal synaptic plasticity and glutamatergic synapses is unknown. Here we present a model of early PD in which a partial denervation, causing mild motor deficits, selectively affects NMDA-dependent LTP but not LTD and dramatically alters NMDA receptor composition in the postsynaptic density. Our findings show that DA decrease influences corticostriatal synaptic plasticity depending on the level of depletion. The use of the TAT2A cell-permeable peptide, as an innovative therapeutic strategy in early PD, rescues physiological NMDA receptor composition, synaptic plasticity, and motor behavior.

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BackgroundHuntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.Methodology/Principal FindingsR6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.Conclusions/SignificanceOur findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington's disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More significantly, our studies point directly to an accessible new therapeutic approach to slow Huntington's disease progression, namely, PDE10A inhibition. There is considerable activity throughout the pharmaceutical industry to develop PDE10A inhibitors for the treatment of basal ganglia disorders. The present results strongly support the investigation of PDE10A inhibitors as a much needed new treatment approach to Huntington's disease.

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The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.