Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A1 and A2A receptor (A1R and A2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A1R and A2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A1R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t(13) = -4.008, p = 0.001). A1R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A1R expression (t(17) = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A2AR expression may be normalized by chronic antipsychotic treatment (F(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.

Altered purinergic receptor expression in the frontal cortex in schizophrenia.

ATP functions as a neurotransmitter, acting on the ubiquitously expressed family of purinergic P2 receptors. In schizophrenia (SCZ), the pathways that modulate extracellular ATP and its catabolism to adenosine are dysregulated. However, the effects of altered ATP availability on P2 receptor expression in the brain in SCZ have not been assessed. We assayed P2 receptor mRNA and protein expression in the DLPFC and ACC in subjects diagnosed with SCZ and matched, non-psychiatrically ill controls (n = 20-22/group). P2RX7, P2RX4 and male P2RX5 mRNA expression were significantly increased (p < 0.05) in the DLPFC in SCZ. Expression of P2RX7 protein isoform was also significantly increased (p < 0.05) in the DLPFC in SCZ. Significant increases in P2RX4 and male P2RX5 mRNA expression may be associated with antipsychotic medication effects. We found that P2RX4 and P2RX7 mRNA are significantly correlated with the inflammatory marker SERPINA3, and may suggest an association between upregulated P2XR and neuroinflammation in SCZ. These findings lend support for brain-region dependent dysregulation of the purinergic system in SCZ.

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.

Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter.

The astrocytic cystine/glutamate antiporter system xc- represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc-, xCT (xCT-/- mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT-/- mice. A proteomic and kinomic screen of the striatum of xCT-/- mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT-/- mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc- plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.

Adenosine Kinase Expression in the Frontal Cortex in Schizophrenia.

The adenosine hypothesis of schizophrenia posits that reduced availability of the neuromodulator adenosine contributes to dysregulation of dopamine and glutamate transmission and the symptoms associated with schizophrenia. It has been proposed that increased expression of the enzyme adenosine kinase (ADK) may drive hypofunction of the adenosine system. While animal models of ADK overexpression support such a role for altered ADK, the expression of ADK in schizophrenia has yet to be examined. In this study, we assayed ADK gene and protein expression in frontocortical tissue from schizophrenia subjects. In the dorsolateral prefrontal cortex (DLPFC), ADK-long and -short splice variant expression was not significantly altered in schizophrenia compared to controls. There was also no significant difference in ADK splice variant expression in the frontal cortex of rats treated chronically with haloperidol-decanoate, in a study to identify the effect of antipsychotics on ADK gene expression. ADK protein expression was not significantly altered in the DLPFC or anterior cingulate cortex (ACC). There was no significant effect of antipsychotic medication on ADK protein expression in the DLPFC or ACC. Overall, our results suggest that increased ADK expression does not contribute to hypofunction of the adenosine system in schizophrenia and that alternative mechanisms are involved in dysregulation of this system in schizophrenia.

Sex differences in DEK expression in the anterior cingulate cortex and its association with dementia severity in schizophrenia.

DEK is a chromatin-remodeling phosphoprotein found in most human tissues, but its expression and function in the human brain is largely unknown. DEK depletion in vitro induces cellular and molecular anomalies associated with cognitive impairment, including down-regulation of the canonical Wnt/ß-catenin signaling pathway. ToppGene analyses link DEK loss to genes associated with various dementias and age-related cognitive decline. To examine the role of DEK in cognitive impairment in severe mental illness, DEK protein expression was assayed by immunoblot in the anterior cingulate cortex (ACC) of subjects with schizophrenia. Cognitive impairment is a core feature of schizophrenia and cognitive function in subjects was assessed antemortem using the clinical dementia rating (CDR) scale. DEK protein expression was not significantly altered in schizophrenia (n = 20) compared to control subjects (n = 20). Further analysis revealed significant reduction in DEK protein expression in women with schizophrenia, and a significant increase in expression in men with schizophrenia, relative to their same-sex controls. DEK protein expression levels were inversely correlated with dementia severity in women. Conversely, in men, DEK protein expression and dementia severity were positively correlated. Notably, there was no sex difference in DEK protein expression in the control group, suggesting that this sex difference is specific to schizophrenia and not due to inherent differences in DEK expression between males and females. These results suggest a novel, sex-specific role for DEK in cognitive performance and highlight a putative sex-specific link between central nervous system DEK protein expression and a neuropsychiatric disease that is commonly associated with cognitive impairment.

Vitamin D metabolite concentrations in umbilical cord blood serum and associations with clinical characteristics in a large prospective mother-infant cohort in Ireland.

Vitamin D deficiency is widespread among mothers and neonates and quality clinical and analytical data are lacking. We used a CDC-accredited LC-MS/MS method to analyze vitamin D metabolites in cord sera from 1050 maternal-infant dyads in the prospective SCOPE Ireland Pregnancy and BASELINE Birth cohort studies, based in Cork, Ireland. The mean±SD total 25(OH)D was 34.9±18.1nmol/L; 35% of cords (50% during winter) had 25(OH)D <25nmol/L, 46% were <30nmol/L and 80% were <50nmol/L. In this predominantly white cohort, the main predictor of cord 25(OH)D [adj. mean difference in nmol/L (95% CI)] was summer delivery [19.2 (17.4, 20.9), P<0.0001]. Maternal smoking during pregnancy (9% prevalence) was negatively associated (P<0.002) with cord 25(OH)D [-4.83 (-7.9, -1.5) nmol/L]. There were no associations between cord 25(OH)D and birth weight or any anthropometric measures at birth. Despite the high prevalence of vitamin D deficiency at birth, there were no documented musculoskeletal complications during infancy, which was likely due to widespread supplementation with vitamin D. The mean±SD concentration of 3-epi-25(OH)D3, detectable in 99.4% of cord samples, was 3.3±1.9nmol/L. The proportion of 25(OH)D as 3-epi-25(OH)D3 was 11.2%. Cord 3-epi-25(OH)D3 concentrations were positively predicted by cord 25(OH)D3 [0.101 (0.099, 0.103) nmol/L, P<0.0001] and negatively by gestational age [-0.104 (-0.131, -0.076) nmol/L, P<0.0001] and maternal age [-0.010 (-0.019, -0.001) nmol/L, P<0.05]. 25(OH)D2 was detected in 98% of cord sera (mean±SD; 2.2±1.9nmol/L) despite low antenatal consumption of vitamin D2 supplements. In conclusion, these first CDC-accredited data of vitamin D metabolites in umbilical cord blood emphasise the high risk of very low vitamin D status in infants born to un-supplemented mothers. Experimental data to define maternal vitamin D requirements for prevention of neonatal deficiency at high latitude are required.