Schizophrenia Research Trends

100Stephen I. Deutsch, John Mastropaolo and Barbara L. Schwartzfacilitation of NMDA receptor-mediated neurotransmission, potentiation of GABAergicneurotransmission, antagonism of AMPA/KA receptors, and “quenching” of locallygenerated reactive oxygen species (Deutsch et al., 2001).An anatomical basis exists for defective GABAergic inhibitory mechanisms inschizophrenia that is independent of NRH, but could also contribute to progressiveexcitotoxicity. Specifically, a significant reduction of GABAergic interneurons in layers II,III, V, and VI of the anterior cingulate has been reported in postmortem brain obtained fromschizophrenia patients (Benes et al., 1992; Coyle, 1996; Jentsch and Roth, 1999).Biochemical data also support defective GABAergic inhibitory mechanisms in schizophrenia,including reduced cortical density of reuptake sites for 3 H-GABA and a reduction in thebinding of 3 H-nipecotic acid, a biochemical marker of the sodium-dependent GABA-reuptakesite, in medial temporal lobe structures (i.e., left polar temporal cortex, and amygdala andhippocampus bilaterally) and basal ganglia. Reduced activity and levels of mRNA forglutamate decarboxylase (GAD), the synthetic enzyme responsible for GABA production,have been reported that could contribute to diminished GABAergic activity (Benes et al.,1992).MOLECULAR GENETIC AND PHARMACOLOGICALINVESTIGATIONS OF NRH AND POSSIBLE MECHANISMS OFPROGRESSIVE EXCITOTOXICITY IN SCHIZOPHRENIAWhen levels of mRNA of the alternatively spliced short and long forms of the gamma 2subunit of the GABA A receptor complex were studied in prefrontal cortex from a postmortemcohort of five schizophrenia patients and five controls (Huntsman et al., 1998), the levels ofthe short form of this subunit were markedly decreased (i.e., 51.7% of control levels) in theschizophrenia patients. The relative overexpression of the long form of the gamma 2 subunitmay result in defective “transduction” of the GABA signal in at least some patients withschizophrenia.Neurons in the cingulate cortex (posterior cingulate/retrosplenial cortex) and othercorticolimbic regions (including piriform cortex, entorhinal cortex, hippocampus andamygdala) are sensitive to toxic intraneuronal vacuolization caused by noncompetitiveNMDA receptor antagonists, such as PCP and MK-801 (dizocilpine) (Olney et al., 1989).Benzodiazepine agonists (i.e., drugs related to diazepam), which potentiate GABAergicinhibitory mechanisms, may protect against this PCP/MK-801-induced toxic intraneuronalvacuolization. Females may be more sensitive to PCP/MK-801-induced damage than males,and dendritic spines may be a specific target. Destruction of dendritic spines would lead to aloss of synaptic complexes and disruption of “connectivity”. Thus, NRH leads to diminishedGABAergic inhibitory tone, whose downstream consequences include toxic intraneuronalvacuolization and destruction of dendritic spines (Coyle, 1996; Farber et al., 1998).Discrete subgroups of schizophrenia patients may exist with NRH (due to diminishedsynthesis or altered “ratios” of specific NMDA receptor subunits resulting in fewerheteromeric NMDA receptors or “combination[s]” with diminished sensitivity to L-