Untitled

112 CHARACTERISTICS OF BRAIN AND BEHAVIORUsing magnetic resonance spectroscopy, glutamate/glutamine has been foundto be significantly higher in the prefrontal cortex of adolescents at high geneticrisk for schizophrenia than in the low-risk offspring, as well as in nontreated adultschizophrenics (Bartha et al., 1997; Tibbo et al., 2004). Moreover, the impairmentof glutamate metabolism also occurs in adult SCZ (Burbaeva et al., 2003). Thesedata demonstrate decreased glutamatergic function in these subjects, as well asthe persistence of such changes throughout the disease. In postmortem DLPFC ofSCZ, NMDA subunit mRNAs are elevated, which suggests a compensatory changeto possibly offset the decrease in glutamate neurotransmission (Dracheva et al.,2001). Evidence of altered AMPA and kainate subunits in the DLPFC (Drachevaet al., 2001; Meador-Woodruff et al., 2001; Mirnics et al., 2000; Vawter et al.,2002a) further implicate the dysregulation of glutamate receptors in the pathologyof schizophrenia. However, expression of AMPAR subunit mRNAs are unchangedin other schizophrenic cohorts (Healy et al., 1998).Previous studies have demonstrated decreased levels of AMPA subunit mRNAsin the temporal lobe and hippocampal subfields (Eastwood et al., 1995b; Gaoet al., 2000; Harrison et al., 1991) and NMDA subunit mRNA in temporal cortex(Hemby et al., 2002b; Humphries et al., 1996). Given that NMDA subunit mRNAlevels are in low abundance in neonates (Law et al., 2003), Harrison and colleaguessuggest that decreased glutamate receptor levels in SCZ may be “recapitulatingan ‘immature’ receptor phenotype.” As noted earlier, NR1 mRNA is posttranscriptionallymodified into various splice variants, all conferring different kineticand pharmacological properties of the receptor.Moreover, GluR1 immunoreactivity is decreased in the parahippocampal gyrus,and GluR2/3 imunoreactivity is decreased in the CA4 subfield (Eastwood et al.,1997b). Others have shown decreased GluR2/3 protein levels in hippocampusand no change in GluR1 or GluR5 protein levels in human postmortem tissue ofSCZ (Breese et al., 1995). Extending these findings, we recently demonstratedsignificant down-regulation of GluR3 mRNA in a specific cell type within the EC(Hemby et al., 2002b). Similar to NMDA subunits, the AMPA subunits are posttranscriptionallymodified into flip and flop variants conferring different pharmacologyand biochemistry to the receptor. Eastwood and colleagues demonstratedan increase in the GluR2 flip/flop ratio in the hippocampal formation of SCZ(Eastwood et al., 1997a). On the other hand, recent data in our laboratory suggestthat flip and flop variants are not altered at a regional level in the DLPFC ofSCZ. Understanding the altered abundance of flip and flop variants in schizophrenicsmay be advantageous for the development of pharmacotherapies selectivefor the variants. Dysregulation of ionotropic glutamate receptors may haveprofound downstream effects, including alterations in excitatory neurotransmissionand subsequent cognitive and behavioral sequelea believed to be driven byglutamatergic circuitry.