Abnormal corticostriatal plasticity is a key mechanism of
L-DOPA-induced
dyskinesia (LID) in
Parkinson's disease (PD). Antagonists at glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (
AMPA) receptors, such as
IEM 1460, reduce induction and expression of
dyskinesia in rat and non-human primate models of PD.
AMPA receptor function is regulated by post-transcriptional splicing of subunit
mRNA to produce flip and flop
isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal
AMPA receptor subunits in the unilateral
6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5 μg
6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute
dyskinesia, rats received
L-DOPA/
benserazide (6/15 mg/kg, i.p.) or vehicle for 21 days. In experiment 2, to assess
dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3 mg/kg, i.p.) for 21 days. Animals were humanely killed 1h following final treatment in experiment 1, and 48 h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using
oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop
isoforms.
L-DOPA treatment increased GluR2-flip
mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable
AMPA receptor antagonist
IEM 1460. GluR1-flip expression was increased after 48 h
drug washout but not in acute LID. There were no changes in expression of flop
isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable
AMPA receptors, which are a potential target of anti-dyskinetic
therapies.