We have emphasized studies on the glutamate systems in brain over the past few years. There are multiple molecules associated with normal glutamatergic neurotransmission. There are multiple glutamate receptors, existing as both subunit-composed ligand-gated ion channels (NMDA, AMPA, and kainate receptors) and seven transmembrane domain receptors (the metabotropic glutamate receptors). There are multiple transporters for glutamate as well, including no fewer than five cell surface expressed transporters, and several vesicular transporters. In addition, there is increasing evidence for the targeting of glutamate receptors to specific synapses, as well as activity-dependent changes in glutamate receptor insertion into the cell membrane, mediated by another family of intracellular proteins. These proteins are selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD-93, PSD-95, SAP102, CIPP, NF-L and yotiao. Many of these recently characterized proteins interact with cell surface proteins, like cell adhesion molecules, ion channels, and glutamate receptors, as well as cytoskeletal elements, and signal transduction molecules. Given the complexity of this neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission hypothesized to exist in schizophrenia. Accordingly, we have begun to comprehensively examine these synaptic molecules in schizophrenia.

Prefrontal Cortical Glutamate Abnormalities in Schizophrenia

We have reported abnormalities of both the NMDA and kainate receptors in the schizophrenic prefrontal cortex. NMDA abnormalities are found in multiple regions of the prefrontal cortex, and are associated primarily with an up-regulation of the NR1 subunit of this receptor family. Kainate receptors are also abnormally expressed, with increased expression of gluR7 mRNA and decreased expression of KA2 mRNA, associated with decreased [3H] kainate binding in multiple regions of the schizophrenic prefrontal cortex.

Thalamus Glutamate Abnormalities in Schizophrenia

Because of the rich reciprocal connection between the prefrontal cortex and the limbic thalamus, we have also explored thalamic expression of molecules of the glutamate synapse.

These have been a particularly fruitful series of investigations, and moves us toward the study of the postmortem brain at the level of an integrated anatomical circuit rather than focusing on single brain areas. We have studied the expression of both the ionotropic and metabotropic glutamate receptors in the schizophrenic thalamus. Interestingly, there are no changes in the expression of metabotropic receptors in the thalamus, although there are striking changes of ionotropic receptors in schizophrenia. In particular, there are changes in the expression of NMDA receptors at the level of the NR1 and NR2C subunits, both of which are decreased in schizophrenia. There are also changes in some but not all of the binding domains associated with the NMDA receptor complex. Finally, we have found abnormalities of NMDA receptor associated intracellular proteins in the thalamus as well.

We have most recently expanded our investigation from the study of glutamate receptors to other molecules associated with the glutamate synapse. We have found alterations of glutamate transporters in schizophrenic thalamus, including both the membrane surface expressed glial EAAT1 and 2 transcripts, as well as one of the vesicular glutamate transporters. Interestingly, the neuronal-associated membrane surface glutamate transporters EAAT3 and 4 are not abnormally expressed. Taken together, these thalamic findings suggest that there are multiple abnormalities of glutamatergic neurotransmission at the level of molecular events in the glutamate synapse in schizophrenia.

We have embarked on a series of experiments to see if these findings are specific to schizophrenia, or generalize to other psychiatric disorders. To that end, we have initiated a series of studies using tissue from the Stanley Foundation Neuropathology Consortium. This tissue set includes subjects not only with schizophrenia, but also with bipolar and major depressive disorders.

Ontogeny of Glutamate Receptors

We have explored the ontogeny of the ionotropic glutamate receptors in human fetal brain, with an emphasis on the developing cortex. Given that schizophrenia is felt to have a neurodevelopmental component, we determined the normal developmental expression of the glutamate receptors in the human cortex. We found evidence that all of the ionotropic glutamate receptors are expressed, but exhibit striking patterns of developmentally specific timing of expression. Of particular interest is the appearance of heightened periods of expression that correlate with known periods of plasticity in the human brain, suggesting a critical role for glutamate in the modulation of neurodevelopmental events. Further, there is significantly increased expression during the second trimester of gestation, particularly for the kainate and NMDA receptors, both of which have been implicated in the pathophysiology of schizophrenia, and we have found both to be abnormally expressed in this illness as described above. This timing correlates with the suspected neurodevelopmental insult in this illness.

Clinical Studies

In collaboration with Dr. Gregory Dalack, we are also involved in a set of studies in living patients with schizophrenia. Driven by the laboratory studies described above, our most recent studies are targeting novel strategies to modulate glutamatergic neurotransmission in these patients, in hopes of improving psychotic symptoms refractory to existing medications.

New approaches to the study of mental illness