Differential modulation of AMPA receptors by cyclothiazide in two types ofstriatal neurons

The modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMP A) receptor-mediated currents by cyclothiazide was investigated in acutely isolated cells from rat striatum with whole-cell patch-clamp recording. Sin gle-cell reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify medium spiny and giant aspiny neurons and to determine their AM PA receptor subunit composition mostly in separate experiments. After pretr eatment with cyclothiazide, kainate-induced AMPA responses were more strong ly potentiated in medium spiny than in giant aspiny neurons; cyclothiazide induced a ninefold leftward shift in the kainate concentration-response cur ve for medium spiny neurons (not giant aspiny neurons). The EC(50)s for the cyclothiazide potentiation did not differ substantially between medium spi ny neurons and giant aspiny neurons. The recovery of kainate-activated curr ents from modulation by cyclothiazide was slower for medium spiny neurons t han for giant aspiny neurons. Medium spiny neurons expressed GluR-A, GluR-B and GluR-C, but not GluR-D subunits in both flip and flop splice variants. All giant aspiny neurons expressed GluR-A and GluR-D, exclusively in the f lop form, half of them also expressed GluR-B and GluR-C. This is in keeping with slow and fast desensitization kinetics in medium spiny neurons and gi ant aspiny neurons, respectively, and differences in cyclothiazide modulati on. The rate of cyclothiazide dissociation from the AMPA receptor, activate d by glutamate, was similar to 90 times slower in medium spiny neurons than in giant aspiny neurons. In giant aspiny neurons (not medium spiny neurons ) this rate was strongly dependent on the presence of an agonist; 1 mm glut amate increased it 30-fold. Thus, two major cell groups in the striatum dis play distinct AMPA receptor compositions carrying specific properties of gl utamate responses. Excitatory transmission will thus be differentially affe cted by cyclothiazide-type compounds.