Abstract
Cultured fibroblasts from first-episode schizophrenia patients (FES) have shown increased susceptibility to apoptosis, which may be related to glutamate dysfunction and progressive neuroanatomical changes. Here we determine whether apoptotic markers obtained from cultured fibroblasts in FES and controls correlate with changes in brain glutamate and N-acetylaspartate (NAA) and regional brain volumes. Eleven antipsychotic-naive FES and seven age- and gender-matched controls underwent 3-Tesla magnetic resonance imaging scanning. Glutamate plus glutamine (Glx) and NAA levels were measured in the anterior cingulate (AC) and the left thalamus (LT). Hallmarks of apoptotic susceptibility (caspase-3-baseline activity, phosphatidylserine externalization and chromatin condensation) were measured in fibroblast cultures obtained from skin biopsies after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 μM. Apoptotic biomarkers were correlated to brain metabolites and regional brain volume. FES and controls showed a negative correlation in the AC between Glx levels and percentages of cells with condensed chromatin (CC) after both apoptosis inductions (STS 0.5 μM: r=−0.90; P=0.001; STS 0.25 μM: r=−0.73; P=0.003), and between NAA and cells with CC (STS 0.5 μM induction r=−0.76; P=0.002; STS 0.25 μM r=−0.62; P=0.01). In addition, we found a negative correlation between percentages of cells with CC and regional brain volume in the right supratemporal cortex and post-central region (STS 0.25 and 0.5 μM; P<0.05 family-wise error corrected (FWEc)). We reveal for the first time that peripheral markers of apoptotic susceptibility may correlate with brain metabolites, Glx and NAA, and regional brain volume in FES and controls, which is consistent with the neuroprogressive theories around the onset of the schizophrenia illness.
Highlights
There were no significant differences between groups in Glx and Fibroblast primary cell culture: markers of apoptotic susceptibility NAA levels either in the anterior cingulate (AC) (controls: 9.2, 1.1; patients: Hallmarks of apoptotic susceptibility (caspase-3 activity, phosphatidylserine externalization and chromatin condensation (CC)) were measured in fibroblast cultures obtained from skin biopsies of all subjects after inducing apoptosis with staurosporine (STS) at doses of 0.25 and 0.5 μM (SigmaAldrich, St Louis, MO, USA)
These biomarkers were chosen on the basis of previous results of increased apoptotic susceptibility in cultured fibroblasts from antipsychotic-naive first-episode schizophrenia patients (FES) patients compared with healthy controls.[15]
Our results showed a negative correlation in the AC between
Summary
Dopaminergic abnormalities are the core feature of psychosis; there are several aspects of schizophrenia that do not appear to be entirely explained by dopamine dysfunction alone.[1]. N-methyl-D-aspartate receptor function has a critical role in synaptogenesis during early development and synaptic elimination during adolescence.[9] The administration of N-methyl-D-aspartate receptor antagonists to experimental animals during early postnatal development results in cortical apoptosis, and behavioral, structural and neurochemical abnormalities associated with schizophrenia.[10,11,12] Deficits in glutamatergic neurotransmission, including NMDA receptor hypofunction and Glu-induced excitotoxicity, are capable of activating apoptosis in neurons, which may lead to neuronal damage and the onset of psychosis in early adulthood.[13,14]
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