Alterations in the inhibitory circuitry of the dorsolateral prefrontal cortex (DLPFC) appear to contribute to the impairments in working memory observed in individuals with schizophrenia. Consistent with this idea, a microarray study indicated that the mRNA levels of GABAA receptor α4 and δ subunits were lower in the DLPFC of subjects with schizophrenia. However, although α4 and δ subunits co-assemble to form functional receptors, the differences in α4 and δ mRNA expression in schizophrenia were not correlated. We assessed the mRNA levels of α4 and δ in the DLPFC of 23 subjects with schizophrenia matched to control subjects by in situ hybridization. The level of α4 mRNA was lower only in subjects with schizophrenia receiving medications at the time of death, whereas the level of δ mRNA was significantly lower in schizophrenia, regardless of the medications used at the time of death. We also found that across postnatal development of monkey DLPFC the level of α4 mRNA decreased with age, whereas that of δ mRNA increased in a manner similar to that previously observed for the α1 subunit. Given that α1 mRNA levels are lower in schizophrenia and α1 subunits can co-assemble with δ subunits, lower δ mRNA in schizophrenia could represent lower GABAA α1βxδ rather than α4βxδ receptors.
Studies suggest that reduced signaling through excitatory synapses, as hypothesized to be present in schizophrenia, give rise to decreased expression of δ subunit mRNA. To test this hypothesis, we measured the levels of δ subunit mRNA in the prefrontal cortex of four rodentmodels of reduced cortical excitatory drive: 1) NMDAR NR1 hypomorphic mice, 2) rats with adult mediodorsal thalamic nuclei lesions, 3) rats with neonatal ventral hippocampal lesions and 4) TrkB hypomorphic mice reported to have decreased dendritic arborization. However, the mRNA levels of δ subunit were unchanged in the PFC of any of the animal models analyzed. Thus, although reduced signaling through excitatory synapses might be a pathogenetic mechanism for other abnormalities in schizophrenia, the convergence of the findings from this study do not support the hypothesis that it accounts for the lower expression of GABAA receptor δ subunit mRNA.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04222008-132139 |
| Date | 16 June 2008 |
| Creators | Maldonado-Avilés, Jaime G. |
| Contributors | David A. Lewis, Jon W. Johnson, Robert A. Sweet, Richard W. Olsen, Gregg E. Homanics, Susan R. Sesack |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04222008-132139/ |
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