Regulation of complexin 1 and complexin 2 in the developing human prefrontal cortex.

Complexin 1 (CX1) and complexin 2 (CX2) are presynaptic proteins that modulate neurotransmitter release and are used as markers of inhibitory and excitatory synapses, respectively. The aim of this study was to gain insight into the development of inhibitory and excitatory synapses in human prefrontal cortex (PFC) by examining the expression of CX1 and CX2 in postmortem tissues. Relative complexin protein levels were measured by Western blotting in postmortem dorsolateral prefrontal cortex (DLPFC) of 42 subjects without neurological or psychiatric disease ranging in age from 18 gestational weeks to 25 years. Samples were batched a priori into fetal, 0-12 month, 1-5 years, 6-10 years, 11-15 years, 16-20 years, and 21-25 years age groups. CX1 and CX2 expression and CX2/CX1 demonstrated a significant effect of age group by ANOVA. Group CX1 level increased progressively across development and was lowest in the fetal group and highest in the young adult group, whereas group CX2 level increased between the fetal and the 6-10 years groups and then plateaued. Consistent with these divergent patterns, there was a significant effect of age group on CX2/CX1, which was higher in fetal and infant groups than in the young adult group. Furthermore, regression analysis demonstrated linear relationships of CX1 and CX2/CX1 with age, whereas CX2 was better described as having a curvilinear relationship with age. These data indicate that complexin expression increases during synaptic maturation in human DLPFC and that an increase in the influence of inhibitory synapses relative to that of excitatory synapses occurs during development in this cortical region.

Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics.

In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects.