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Molecular Abnormalities of the Glutamate Synapse in the Thalamus in Schizophrenia
Author(s) -
MEADORWOODRUFF JAMES H.,
CLINTON SARAH M.,
BENEYTO MONICA,
McCULLUMSMITH ROBERT E.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1300.005
Subject(s) - postsynaptic density , ampa receptor , glutamate receptor , silent synapse , neurotransmission , kainate receptor , biology , microbiology and biotechnology , metabotropic glutamate receptor , postsynaptic potential , nmda receptor , metabotropic glutamate receptor 7 , synapse , metabotropic glutamate receptor 6 , glutamatergic , neuroscience , metabotropic glutamate receptor 1 , chemistry , receptor , biochemistry
A bstract : Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre‐ and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface‐expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor‐related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF‐L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor‐related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.