BRAIN RESEARCH ELSEVIER Brain Research 647 (1994) 209-219 Research Report Glutamate receptor expression in rat striatum: Effect of deafferentation Ullrich Wiillner, David G. Standaert, Claudia M. Testa, G. Bernhard Landwehrmeyer, Maria Vincenza Catania, John B. Penney Jr., Anne B. Young * Neurology Sen'ice, Massachusetts General Hospital, and Harvard Medical School, Fruit Street, Boston, MA 02114, USA Accepted 15 February 1994 Abstract The cerebral cortex is the primary source of glutamatergic afferents to the neostriatum. We used in situ hybridization to examine the effect of removal of the glutamatergic input to the striatum by unilateral frontal cortical ablation on the expression of genes encoding subunits from three families of glutamate receptors: N-methyl-D-aspartate receptors (NMDAR1, NMDAR2A, and NMDAR2B); a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (GluR1-4, flip and flop splice variants); and metabotropic receptors (mGluR1-5). Significant changes were restricted to the dorsolateral quadrant of the ipsilateral striatum, the main projection area of the sensorimotor cortex. The expression of those messages which are normally abundant, NMDAR1, NMDAR2A, GIuR1-4 flop and mGluR1, 3 and 5, was decreased in the deafferented dorsolateral striatum by 10-39% at 3 days after cortical ablation and subsequently increased to 120-165% of control at 15 and 60 days. mRNAs encoding the flip isoforms of GIuR1-4, mGluR2 and 4, and an alternatively spliced region of NMDAR1 (Insertion I) which are undetectable or present at low levels in the striatum were not induced by cortical ablation. In contrast, both glial fibrillary acid protein and /3-actin mRNA expression were markedly enhanced at 3 and 15 days, returning to near normal at 60 days. Striatal NMDA, AMPA and metabotropic type 1 ligand binding sites were increased as early as 3 days after cortical ablation, reached a peak at 15 days and remained increased for up to 60 days, while metabotropic type 2 binding was slightly but significantly reduced at 3 and 15 days and [3H]kainate binding did not change significantly. These results demonstrate that cortical ablation, and subsequent loss of glutamatergic afferents to the striatum, results in alterations in the expression of genes encoding glutamate receptor subunits in striatal neurons. The regulation of these genes appears to be coordinate, so that the relative abundance of the different messages is preserved. Key words: N-methyl-D-aspartate; AMPA; Kainate; Metabotropic; Decortication; Neostriatum 1. Introduction The striatum receives a large and highly ordered excitatory amino acid (EAA) projection from the entire cerebral cortex [9,18,43]. Ablation of a frontal hemicor- tex leads to a significant decrease in glutamate levels and [3H]glutamate uptake in the ipsilateral striatum [6,15]. Experimental data indicate that the corticostri- atal projection has an important role in the regulation of striatal neuropeptide levels; also, glutamic acid de- carboxylase (GAD) mRNA expression in the striatum is altered after a cortical lesion [30,33,40]. * Corresponding author. Fax: (1) (617) 726-2353. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)00239-9 The effects of glutamate on striatal neurons are mediated via the ion channel-coupled N-methyl-D- aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-iso- xazolepropionate (AMPA) and kainate (KA) receptors, and the G-protein-coupled metabotropic (mGluR) classes of EAA receptors; high affinity binding sites for all four classes have been demonstrated in the striatum [2,44]. Ligand binding studies of striatal EAA receptors after deafferentation have yielded inconsistent results. After mechanical removal of the ipsilateral hemicortex, total [3H]glutamate binding was found to be increased to 123-134% of control [7,29] or unchanged [19], [3H]AMPA binding was either decreased by 30% [8]or unchanged [12], [3H]CPP binding (to NMDA recep- tors) was increased to 113-135% [31] while for NM-