GLUR2 GLUTAMATE-RECEPTOR SUBUNIT FLIP AND FLOP ISOFORMS ARE DECREASEDIN THE HIPPOCAMPAL-FORMATION IN SCHIZOPHRENIA - A REVERSE TRANSCRIPTASE-POLYMERASE CHAIN-REACTION (RT-PCR) STUDY

GluR2 is the key subunit of heteromeric AMPA-preferring glutamate rece ptors. GluR2 mRNA has been shown by in situ hybridization histochemist ry to be decreased in the hippocampal formation in schizophrenics. Her e, a quantitative reverse transcriptase-polymerase chain reaction (RT- PCR) method was used to investigate GluR2 expression further and to ex amine the relative abundance of its alternatively spliced mRNA isoform s ('flip' and 'flop') in 11 schizophrenics and 11 matched controls. Co mpared to the controls, schizophrenics showed reduced expression of bo th isoforms relative to cyclophilin mRNA, but a greater loss of the fl op isoform led to a higher flip:flop ratio. These differences were obs erved having controlled for the confounding effects of brain pH and ag e upon the mRNAs. We also found that the abundance of GluR2 mRNA corre lates with that of the encoded subunit. This study has confirmed that, in schizophrenia, hippocampal GluR2 mRNA is reduced, and indicates th at GluR2 subunits are composed of a higher proportion of the flip vari ant. These data extend the evidence for glutamatergic dysfunction in t he disease. They suggest that signal transduction through hippocampal AMPA receptors is impaired in schizophrenia bath by an overall loss of GluR2 expression, and by the change in flip:flop ratio which is predi cted to alter the desensitization kinetics of the remaining GluR2 subu nits.