Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.
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.
Institute of Brain, Behaviour and Mental Health, University of Manchester, UK. christopher.kobylecki@manchester.ac.uk
Christopher
C
Kobylecki
Alan R
AR
Crossman
Paula
P
Ravenscroft
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013565:Sympatholytics / Q000633:toxicity
D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; C110702:IEM 1460; D007456:Iodine Isotopes; D012333:RNA, Messenger; D018091:Receptors, AMPA; D013565:Sympatholytics; C079213:RTI 121; D007980:Levodopa; D016627:Oxidopamine; D003042:Cocaine; D000218:Adamantane
Animal models; Calcium; Glutamate; L-DOPA-induced dyskinesia; Parkinson's disease; Splicing; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid