Supplement: Molecular Mysteries

1,2 "They have positive symptoms, they have negative symptoms, they have cognitive deficits that look very much like what you see in schizophrenia," says NYU's Javitt. For example, NMDA receptors are involved in the formation of memories but not in the retention of old memories; similarly, patients with schizophrenia have trouble forming, but not retaining, memories, Javitt says. NMDA receptors are also involved in pitch matching in the auditory cortex and in certain visual tasks, and schiz

Dec 1, 2007
Melinda Wenner
1,2 "They have positive symptoms, they have negative symptoms, they have cognitive deficits that look very much like what you see in schizophrenia," says NYU's Javitt.

For example, NMDA receptors are involved in the formation of memories but not in the retention of old memories; similarly, patients with schizophrenia have trouble forming, but not retaining, memories, Javitt says. NMDA receptors are also involved in pitch matching in the auditory cortex and in certain visual tasks, and schizophrenia patients have trouble detecting changes in pitch and in performing certain visual tasks.

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Schizophrenia in the prefrontal cortex
Postmortem studies have reported that subjects with schizophrenia have (1) fewer neurons in the mediodorsal (MD) thalamic nucleus; (2) diminished density of certain parvalbumin-positive synapses where MD neurons project into the prefrontal cortex (PFC); (3) lower spine density on the basilar dendrites of deep layer 3 pyramidal neurons, the principal targets of excitatory synaptic projections from the MD; (4) reduced mRNA expression of GABA-synthesizing glutamic acid decarboxylase (GAD67) in a subset of PFC GABAneurons; (5) decreased density of GABA transporter (GAT-1)-immunoreactive axon cartridges, the axon terminals of GABAergic chandelier neurons, which synapse exclusively on pyramidal neurons; and (6) decreased dopamine innervation in layer 6, where pyramidal neurons provide corticothalamic feedback projections.
Source: Neuron, 28;325-34, 2000.

To confirm that these symptoms are caused by the drug itself rather than by factors associated with drug abuse, John Krystal, a clinical pharmacologist and psychiatrist at Yale University, administered low doses of ketamine to healthy subjects in 1992 and achieved similar results.3 Krystal points out, however, that administering ketamine is not the same thing as having schizophrenia. "It mainly produces this one effect of blocking NMDA glutamate receptors, and schizophrenia is very likely to affect, in primary ways, multiple systems of the brain."

Some studies suggest that chronic NMDA receptor deficits do affect multiple brain systems, including dopamine. Research shows, for example, that disturbances in glutamate and NMDA function can lead to the type of dopamine dysregulation seen in schizophrenia,4 that overstimulation of dopamine D2 receptors affects NMDA function adversely in subcortical regions,5 and that stimulating NMDA receptors increases dopamine D1 levels,6 according to Abi-Dargham.

Genetic evidence also points to the glutamate system. Genes for dysbindin and neuregulin 1, proteins that indirectly modulate NMDA function, have both been implicated in schizophrenia. Harvard's Coyle points out that of 15 schizophrenia-associated genes mentioned in a recent peer-reviewed journal article, "About five of them were within two degrees of separation of the NMDA receptor."7

"You kind of [had to] scratch your head and say, 'hmm, maybe we've been barking up the wrong tree for a long time'" --Joe Coyle

That said, most of the evidence implicating NMDA in schizophrenia has been based on pharmacologic evidence, says David Lewis, a psychiatrist at the University of Pittsburgh. "There really is no body of literature directly showing that the NMDA receptor is altered in the illness," he says. "It's an important and interesting hypothesis, [and] there are some data that are consistent with it, but it doesn't have the sine qua non of a pathological entity yet." (For more on Lewis' GABA research, see 8-10. Other studies suggest that sensory gating, a function related to attention and the ability to filter out extraneous information, is deficient in individuals with schizophrenia; the alpha7 receptor also mediates this process.11 Abnormal muscarinic cholinergic receptors have been implicated in the disorder, too. "The implication is that [for] those patients who do not respond well to a dopamine antagonist, adding a cholinergic agent could be beneficial," says Rajiv Tandon, a psychiatrist at the Florida Department of Children and Families in Tallahassee.

With so many discrete systems implicated in schizophrenia, it's difficult to know what might ultimately "cause" the disorder. "[Some] people say schizophrenia is a glutamate disease, ... [while others] say it's a GABA disease, and [still others] say it's a dopamine disease," says Lewis. Yet, he says that these different molecular views can be integrated. Some of the most exciting areas of research today, he says, involve finding ways in which these different systems might converge upon a common problem in cortical circuitry; doing so would obviously have profound implications for treatment development.

The key lies in using a combination of different approaches, such as imaging, animal studies, and postmortem studies, to decipher which of the findings represent causes, consequences, compensations, and confounds. For instance, explains Lewis, if a scientist sees that two findings are correlated, such as NMDA hypofunction and deficits in GABA synthesis, he or she could decrease the function of NMDA receptors in animal models to determine whether a GABA deficit ensues, or vice versa. If one change consistently follows the other but not the other way around, then causality begins to become clearer.

Tandon agrees that it's crucial to look at the big picture. "It's one illness we're talking about, so we've really got to try to pull all these findings together," he says. "Efforts to pull all these together [and] organize them around some conceptual framework, that's something I think we need to be spending a little more time and effort on," he says.

1. R.M. Allen, S.J. Young, "Phencyclidine-induced psychosis," Am J Psychiatr, 135:1081-4, 1978.
2. D.C. Javitt et al., "Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia," Hillside J Clin Psych, 9:12-35, 1987.
3. J.H. Krystal et al., "Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses," Arch Gen Psych, 51:199-214, 1994.
4. J.D. Jentsch, R.H. Roth, "The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia," Neuropsychopharmacol, 20:201-25, 1999.
5. M.S. Levine et al., "Neuromodulatory actions of dopamine on synaptically-evoked neostriatal responses in slices," Synapse, 24:65-78, 1996.
6. L. Scott et al., "Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation," Proc Natl Acad Sci, 99:1661-4, 2002.
7. Medscape Psychiatry & Mental Health, "Expert interview: treating the negative symptoms of schizophrenia: an expert interview with Joseph Coyle, MD," posted Nov. 13, 2006. www.medscape.com/viewarticle/546990
8. J. Court et al., "Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus," J Neurochem, 73:1590-7, 1999.
9. R. Freedman et al., "Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia," Biol Psychiatry, 38:22-33, 1995.
10. A. Marutle et al., "Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia," J Chem Neuroanat, 22:115-26, 2001.
11. R. Freedman et al., "Schizophrenia and nicotinic receptors," Harvard Rev Psych, 2:179-92, 1994.