None of the subjects had histories of neurological or psychiatric conditions other than schizophrenia, and none displayed neuropathological abnormalities such as gross cell loss, infarcts, or unusually high densities of amyloid plaques, neurofibrillary tangles, or Lewy bodies. Nor were significant correlations found between antipsychotic dosages of our schizophrenia cases a month prior to death and dysbindin-1 isoform levels, a finding in accordance with an earlier study by our group. This is consistent with studies demonstrating that chronic haloperidol administration in mice has no significant effect on dysbindin-1 gene or protein expression. Finally, our findings were not attributable to loss of synapses in the schizophrenia cases for three reasons. First, protein assay data on all synaptosomal samples were used to load the same amount of synaptic protein in the Western blots. Second, to correct for any loading errors, the dysbindin-1 isoforms levels analyzed were those normalized to synaptosomal levels of b-actin in each sample. Third, the synaptosomal fractions of our normal and schizophrenia cases showed no significant differences in either the synaptic vesicle marker synaptophysin or the postsynaptic marker PSD-95. The lack of differences between normal and schizophrenia cases in synaptophysin was observed previously in our quantitative immunohistochemical study of dysbindin-1 in the HF. In the case of ClC6, existing studies examining CNS expression of this protein did not look at Pimozide retinal expression explicitly so it is possible that ClC6 distribution in the retina differs from that of other areas of the CNS. ClC3, however, has been shown to be expressed in synaptic layers of the mouse retina in contrast to our finding of low apparent ClC3 expression in chicken retina. It is possible that this -Pugnac-chemical-structure.gif)
difference reflects a true species difference. It is also possible that our ClC3 antibody did not have the same level of affinity for the protein. Arguing Dexrazoxane hydrochloride against this interpretation, a monoclonal antibody specific for a different region of the ClC3 protein also minimally labeled the chicken retina. Furthermore, this monoclonal antibody was raised against the same region of rat ClC3 as the polyclonal antibody that strongly labeled the synaptic layers of mouse retina in refs.19 and 50. The antigens used to synthesize both ClC3 antibodies were derived from portions of the rat protein sequence that are 100% identical to the predicted chicken amino acid sequence for ClC3. The differences in transcriptional profiles could be explained by several factors including experimental conditions, type of array technology and intrinsic differenced between isolates used in all three studies. Virulence and tissue burden quantitative assays performed in this study support the idea that CgCDR1 and PUP1 are important for the pathogenesis of C. glabrata at some stage of the infection. Currently our data cannot discriminate whether or not C. glabrata can replicate in the tested animal models. At least, the tested strains can persist over the time course of the experimentation, which is consistent with similar experiments performed in mice. Interestingly, enhanced virulence has been observed in other C. glabrata isolates where azole resistance results from mitochondrial dysfunctions independently of GOF CgPDR1 mutations. In this case, CgCDR1 and PUP1 are strongly upregulated and thus may also contribute to favor C. glabrata in host interactions. The specific role of individual gene in fungal-host interaction remains to be solved however several reports have already identified ABC-transporters as able to contribute to selective advantages under host conditions. For example, the Cryptococcus neoformans ABC transporter AFR1 was shown to interfere with lysosome acidification in macrophages to increase its survival. In particular, azole-resistant isolates showing increased AFR1 expression were more virulent than their parental azole-susceptible isolates, which highlights the relevance of the association between drug resistance and virulence observed here.