Faculty Bibliography

BACKGROUND: Several lines of evidence indicate the altered function of the temporal lobe, including the hippocampus and entorhinal cortex (EC), is associated with schizophrenia. We used single-cell gene expression technologies to assess coordinate changes in the expression of multiple genes, including neuronal signaling and synaptic-related markers in EC layer II stellate neurons. METHODS: We used a single-neuron microdissection technique coupled with linear antisense RNA amplification and high density/candidate gene arrays to assess coordinate changes in gene expression. The expression and relative abundance of more than 18,000 messenger RNAs were assessed from EC layer II stellate neurons from postmortem samples of schizophrenic and age-matched control brains. Results of this initial screen were used to perform a more specific secondary messenger RNA screen for each subject. RESULTS: Data disclosed marked differences in expression of various G-protein-coupled receptor-signaling transcripts, glutamate receptor subunits, synaptic proteins, and other transcripts. Results of secondary screening showed significant decreases in levels of G-protein subunit i(alpha)1, glutamate receptor 3, N-methyl-D-aspartate receptor 1, synaptophysin, and sensory nerve action potentials 23 and 25 in the stellate neurons of schizophrenic patients. We observed down-regulation of phospholemman (a phosphoprotein associated with anion channel formation) messenger RNA and protein levels in layer II/III stellate neurons in the population with schizophrenia. CONCLUSIONS: These results provide a preliminary expression profile of schizophrenia in defined neuronal populations. Understanding the coordinated involvement of multiple genes in human disease provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention.

We used the fimbria-fornix (FF) transection model of axonal injury to test the hypothesis that transneuronal degeneration occurs in the adult central nervous system in response to deafferentation. The medial mammillary nucleus, pars medialis (MMNm) was analyzed by light and electron microscopy at 3, 7, 14, and 30 days, and 6 months after unilateral FF transection in adult rat to identify the time course of neuronal responses in a remote target. Presynaptic terminals and neuronal cell bodies degenerated in the MMNm ipsilateral to FF transection. Terminal degeneration occurred predominantly at 3 and 7 days postlesion. Between 14 and 30 days postlesion, neuronal number in the MMNm decreased (approximately 20%). Two forms of neuronal degeneration were found in the MMNm after deafferentation. Some neurons died apoptotically. Other neurons underwent vacuolar degeneration. In these latter neurons, somatodendritic pathology occurred at 14 and 30 days and 6 months postlesion. The ultrastructure of this vacuolar degeneration was characterized by disorganization of the cytoplasm, formation of membrane-bound vacuolar cisternae and membranous inclusions, loss of organelles, cytoplasmic pallor, and chromatin alterations. This study shows that both anterograde axonal degeneration and transneuronal degeneration occur in a fornical target after FF axon transection. This transneuronal degeneration can be classified as sustained neuronal atrophy or transsynaptic apoptosis.