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Posted 24 July 2008
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Glutamate From a Cortical Perspective
As opposed to dopaminergic models, which view signs and symptoms of schizophrenia as resulting from primary dopaminergic dysfunction, glutamatergic models view schizophrenia as resulting from dysfunction converging at glutamatergic synapses in general and NMDA receptors in particular. NMDA models of schizophrenia were first proposed about 20 years ago (Javitt, 1987; Javitt and Zukin, 1991). The main question is how these models help explain the complex features of schizophrenia, and what predictions can be made regarding psychopathology based upon glutamatergic concepts.
Regional implications of the glutamatergic model
Although some regions, such as prefrontal cortex, are more studied in schizophrenia than others, in fact no studies in schizophrenia have demonstrated preferential involvement of any single brain regions. Further, when widespread neurocognitive batteries are used, such as the recently developed MATRICS Consensus Cognitive Battery (Kern et al., 2008), studies routinely show diffuse deficits across a wide range of neurocognitive domains (e.g., Saykin et al., 1991; Bilder et al., 2000), irrespective of brain region, consistent with glutamatergic models.
Memory dysfunction as a core feature of schizophrenia
NMDA dysfunction as mediator of prefrontal deficits in schizophrenia
Cortical dysfunction within sensory brain regions
In auditory cortex, deficits are observed in the generation of a specific event-related potential (ERP) component termed mismatch negativity (MMN). MMN is generated within primary auditory cortex and reflects activity of NMDA-dependent "mismatch" detectors that detect alterations in ongoing patterns of acoustic stimulation (Javitt et al., 2008). Schizophrenia-like deficits can be induced in both human (Umbricht et al., 2000) and animal (Javitt , 2000) models by NMDA antagonists such as PCP or ketamine. Impairments in early visual processing have also been documented in schizophrenia and shown to correspond to the pattern expected from local NMDA dysfunction (Butler et al., 2005). In both cases, impairments in early stages of sensory processing contribute to higher order impairments such as difficulties in detecting emotion based upon tone of voice (prosody) (Leitman et al., 2007), in recognizing fragmented objects (Doniger et al., 2002), or in orthographic and phonological aspects of reading (Revheim et al., 2006).
Over the last several years, histological studies of primary auditory (Sweet et al., 2007) and visual (Dorph-Petersen et al., 2007) regions have also documented local structural deficits similar to those observed in higher order brain regions such as PFC, further supporting the concept of generalized cortical pathology in schizophrenia. Several histological deficits considered characteristic of schizophrenia, such as reduced parvalbumin expression in GAD67 interneurons, can be induced by subchronic administration of NMDA antagonists in animal models (Behrens et al., 2007), suggesting that these may also be viewed as "downstream" of a primary NMDA mechanism.
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