Reduced expression of synaptic and plasticity-related proteins in OB in schizophrenia suggests alterations in the synaptic machinery. Dysfunctional synapses between ORNs and target cells during development and throughout life may be responsible for the reduced OB volume and the olfactory deficits observed in schizophrenia. Understanding the mechanisms and consequences of this dysfunction is essential to the development of better treatment for schizophrenia. It is our hypothesis that in schizophrenia, synapses of the ORNs with their OB targets are hypofunctional. Hypoglutamatergic transmission at these synapses results in an impairment of long-term potentiation in the OB. While preliminary results suggest that this hypothesis is valid, it warrants further study.
In aim 1, we will show evidence of hypoglutamatergic transmission at the synapses between ORNs and their OB targets in schizophrenia. These synapses are located in discreet spherical composites of pre- and post-synaptic elements called glomeruli. We will use quantitative radioimmunohistochemistry to test the hypothesis that there is a decreased expression of some subtypes of NMDA, AMPA or Group1 metabotropic glutamate receptors in OB glomeruli from individual with schizophrenia. We will also use a novel proteomic method, immunodetection amplified with T7 polymerase (IDAT) to investigate a shift in subunit composition away from NMDAR2 B subtype and toward gluR2 subtype. We expect glutamate receptors, in particular the NMDA receptors, to be down regulated in OB glomeruli in schizophrenia. Glutamatergic function is essential to the induction and maintenance of LTP. Several proteins, including syntaxin, brain-derived neurotrophic factor (BDNF), nitric oxyde synthetase (NOS) and activity-regulated cytoskeleton-associated protein (arc) are up-regulated following the induction of LTP and can serve as markers for that form of synaptic plasticity. We will look at the expression of these selected LTP markers in OB glomeruli with quantitative radioimmunohistochemistry. We will also use IDAT to examine the coordinate expression of glutamate receptors and LTP markers in the same glomeruli. We expect LTP markers to be down regulated in glomeruli in schizophrenia. We also expect a correlation between the expression of NMDA receptors and LTP markers. A correlation between glutamatergic function, LTP markers and schizophrenia will better define the role of these proteins in the olfactory deficits observed in schizophrenia. The effect of the antipsychotic on the expression of these proteins will also be investigated in mice chronically treated with haloperidol to discriminate between disease- and treatment related changes.
