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Transcriptional Regulation in Schizophrenia 111episodes and induce behavioral and cognitive deficits that can be attenuated byantipsychotic administration (Lahti et al., 1995; Malhotra et al., 1997).As mentioned previously, glutamate is a major transmitter in the EC and DLPFCand is involved in the ability of the synapse to change its function and activity—making it an interesting candidate for investigation in the pathology of schizophrenia.Glutamate exerts its effects by interacting with receptors to generate acellular response. The primary type of receptors with which glutamate interactsare ionotropic receptors: classified as N-methyl-D-aspartate (NMDA; comprisedof combinations of NR1, NR2A-D, NR3A,B subunits), (±)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; comprised of GluR1-4 subunits), andkainate (GluR5-7, KA1-2), based on their pharmacological characteristics andsequence information (Borges & Dingledine, 2002; Hollmann & Heinemann,1994). All three receptor types are thought to play roles in long-term potentiation,a well studied form of synaptic plasticity (Bortolotto et al., 1999; Nestler,2001; Ungless et al., 2001). NMDA, AMPA, and kainite receptors are ion channelsformed from some combination of NMDA, AMPA, or kainite receptor subunits,respectively. A distinct gene encodes each of these subunits. Transcriptionalregulation within the cell determines the expression level of the specific subunitsavailable to interact and form functional receptors, and subunit composition altersthe properties of the receptor.NMDA receptors mediate slower and more long-lasting neuronal excitabilityby allowing more calcium ions to flow into the neuron. Subunit compositionof the NMDA receptor affects how NMDA receptors interact with glutamateand subsequently how NMDA receptors mediate cellular excitability. In addition,the genes encoding certain NMDA subunits can be alternatively spliced togenerate distinct variants of the subunit. These splice variants provide differentdegrees of control over the function of the receptor (Dingledine et al., 1999;Hollmann et al., 1993; Koltchine et al., 1996; Traynelis et al., 1995). In contrastto NMDA receptors, AMPA receptors contribute to fast neuronal excitation.Subunit composition of the AMPA receptor contributes to functional propertiesof the receptor, such as the ability of calcium to enter the neuron and increaseneuronal excitability (Burnashev et al., 1992; Jonas et al., 1994). LikeNMDA subunits, AMPA and kainite receptors exist in different splice-variantforms that alter the amount of time these receptors stay open (and thus changeneuronal excitability; Koike et al., 2000; Mosbacher et al., 1994). Studies havefound the expression of the genes encoding these splice variants differ in ratiodepending on development, drug administration, and disease state (Eastwoodet al., 1997a; Monyer et al., 1991). Because subunit composition determines thefunctional properties of ionotropic glutamate receptors (Borges & Dingledine,2002), alterations in expression of specific subunits could have profound influenceson neurotransmission underlying biochemical and behavioral effects associatedwith schizophrenia.