In:
European Journal of Neuroscience, Wiley, Vol. 22, No. 1 ( 2005-07), p. 247-256
Abstract:
Nigrostriatal dopamine depletion disrupts striatal medium spiny neuron morphology in Parkinson's disease and modulates striatal synaptic plasticity in animal models of parkinsonism. We demonstrate that long‐term nigrostriatal dopamine depletion in the rat induces evolving changes in the phosphorylation of striatal proteins critical for synaptic plasticity. Dopamine depletion increased the phosphorylation of the alpha isoform of calcium–calmodulin‐dependent protein kinase II (CaMKIIα) at Thr 286 , a site associated with enhanced autonomous kinase activity, but did not alter total levels of CaMKIIα or other synaptic proteins. Dopamine depletion decreased CaMKIIα levels in postsynaptic density‐enriched fractions without significant changes in other proteins. The activity of protein phosphatase 1 (PP1), a postsynaptic phosphatase that dephosphorylates CaMKII, is regulated by DARPP‐32 (dopamine‐ and cAMP‐regulated phosphoprotein of 32 kDa). Dopamine depletion had no effect on DARPP‐32 phosphorylation at Thr 34 , but increased DARPP‐32 phosphorylation at Thr 75 . Levodopa administration reversed the increased phosphorylation of both CaMKIIα and DARPP‐32. Normal ageing increased the levels of PP1(γ1 isoform) but decreased levels of the PP1γ1‐targeting proteins spinophilin and neurabin. Elevated phosphorylations of CaMKIIα and DARPP‐32 were maintained for up to 20 months after dopamine depletion. However, phosphorylation of the CaMKII–PP1 substrate, Ser 831 in the glutamate receptor GluR1 subunit, was increased only after sustained (9–20 months) dopamine depletion. Interaction of ageing‐related changes in PP1 with the dopamine depletion‐induced changes in CaMKIIα may account for enhanced GluR1 phosphorylation only after long‐term dopamine depletion. These evolving changes may impact striatal synaptic plasticity, Parkinson's disease progression and the changing efficacy and side‐effects associated with dopamine replacement therapy.
Type of Medium:
Online Resource
ISSN:
0953-816X
,
1460-9568
DOI:
10.1111/ejn.2005.22.issue-1
DOI:
10.1111/j.1460-9568.2005.04190.x
Language:
English
Publisher:
Wiley
Publication Date:
2005
detail.hit.zdb_id:
2005178-5
SSG:
12
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