Posted 24 July 2008

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Glutamate From a Cortical Perspective
By Daniel Javitt

Daniel Javitt

As discussed by Dr. Moghaddam in a prior Schizophrenia Research Forum hypothesis review, glutamatergic hypotheses of schizophrenia are based upon the ability of NMDA receptor antagonists, such as phencyclidine (PCP), ketamine, or MK-801, to induce psychotic symptoms closely resembling those of schizophrenia. As opposed to dopaminergic agents, such as amphetamine, NMDA antagonists induce

negative and cognitive symptoms, as well as positive symptoms, and also recreate levels of cognitive dysfunction observed in schizophrenia. Thus, a single, discrete intervention can recreate many, if not all, of the most characteristic features of schizophrenia.

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
One key difference between the glutamate and dopamine models concerns regional brain involvement. Dopaminergic systems project primarily to striatal, limbic, and frontal brain regions, potentially accounting for the extensive degree to which these systems have been studied in schizophrenia. In contrast, glutamatergic systems in general, and NMDA receptors in particular, are widely distributed throughout brain (Fig. 1), with considerable density throughout cortex and subcortical structures. Thus, a key difference between glutamatergic and dopaminergic models is that glutamatergic models would predict dysfunctional circuitry throughout brain, particularly in brain processes requiring NMDA involvement, whereas dopaminergic models would predict dysfunction primarily in those regions receiving primary dopaminergic innervation.

Figure 1
In situ hybridization map of NR1 subunit showing high density throughout mouse cortex (CTX), olfactory turbercle (OT), hippocampus CA3 (H), caudate/putamen (CP), and thalamus (Thal). [From www.brain-map.org]

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
The best studied function of NMDA receptors in brain is in hippocampus, where NMDA receptors serve as the trigger for hippocampal long-term potentiation (LTP) (Cotman and Monaghan, 1988). In animals, infusion of NMDA antagonists directly into hippocampus leads to impaired ability to learn new information, while having little effect upon retention of previously learned information (Morris, 1989). This distinction arises because new memory formation depends upon LTP initiation—an NMDA-dependent phenomenon—while memory retention depends only on non-NMDA-dependent consolidation processes. In humans, NMDA antagonists also produce a well-documented amnestic effect, with impairment in encoding but not retention (Honey et al., 2003). One clear prediction of the glutamate model, therefore, is that patients with schizophrenia should show impaired ability to learn new information, with relatively preserved ability to maintain information once it has been learned. In fact, numerous studies have now shown that deficits in learning and memory are among the most consistently disturbed features of schizophrenia, and that patients do indeed show the pattern expected from NMDA dysfunction (i.e., similar deficits at short and long retention intervals) rather than hippocampal structural damage (i.e., deficits in retention as well as encoding). Compared to glutamatergic agents, dopamine agonists and antagonists produce relatively limited effects on learning and memory.

NMDA dysfunction as mediator of prefrontal deficits in schizophrenia
A second area in which glutamatergic models help to explain the pathophysiology of schizophrenia is the realm of higher order cortical dysfunction. Schizophrenia is associated with deficits in well-known higher order processes such as executive processing or attention. As with learning and memory, deficits in these types of processes can be recreated by NMDA blockade in human or animal models. For example, ketamine challenge in humans leads to impaired performance on tests such as the Wisconsin Card Sorting Test (WCST) (Krystal et al., 2005) or the AX-type continuous performance task (AX-CPT) (Umbricht et al., 2000), two widely used measures of executive processing dysfunction in schizophrenia. Similar deficits are not seen following challenge with amphetamine. Although deficits in executive processing are typically interpreted as showing dysfunction of prefrontal cortex or fronto-parietal circuits, a more precise interpretation may be that such deficits reflect dysfunction of NMDA receptors within those brain regions. Other aspects of prefrontal function, such as ability to ignore distraction across delay (Rabinowicz et al., 2000), are paradoxically preserved in schizophrenia. As with learning and memory deficits, therefore, executive processing deficits may be most parsimoniously attributed to underlying NMDA dysfunction.

Cortical dysfunction within sensory brain regions
A final test of the glutamate model comes from studies of cortical processing deficits within sensory regions. Sensory regions of the brain, such as primary auditory and visual cortex, have been traditionally understudied in schizophrenia, presumably because of assumptions, going back at least to Bleuler, that sensory processes in schizophrenia are intact. In fact, however, significant deficits in cortical information processing can be demonstrated even at the level of primary and secondary sensory cortices, consistent with the widespread distribution of NMDA receptors in brain.

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.

Summary
Overall, the importance of the glutamatergic or PCP/NMDA model of schizophrenia is at least twofold. First, it highlights that one single intervention (blockade of the NMDA receptor) can reproduce key features of schizophrenia, and points therefore to NMDA dysfunction as a potential final common mechanism leading to symptoms and cognitive dysfunction in schizophrenia. Second, however, it highlights the importance of viewing schizophrenia as a generalized brain disorder with involvement of sensory as well as higher order brain regions. To the extent that schizophrenia is a "whole brain" disorder, both pharmacological and remediative strategies need to target basic, sensory-level processes as well as more complex neurocognitive deficits. At present, as noted by Dr. Moghaddam, potential causes of NMDA dysfunction in schizophrenia are under active investigation, with contributions likely to be found from both genetic and environmental factors. Further, the ideal targets for intervention may not be the NMDA receptor itself, but may be surrounding molecules within the glutamate synapse, such as glycine transporters or metabotropic glutamate receptors. Nevertheless, glutamatergic models are critical for drawing attention not only to synapses other than those which have been the traditional targets of schizophrenia investigations, but also to entirely different brain regions, leading to a paradigm shift in schizophrenia research.

References:
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