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 A_2A receptor (A₁R and A_2AR) 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 A_2AR 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 A_2AR mRNA expression (Spearman’s r = 0.424, p = 0.009). A_2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A_2AR 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.

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia (n = 20) and sex- and age-matched control subjects without psychiatric illness (n = 20) was obtained from the Bronx–Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components—adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5′-nucleotidase (NT5E)—were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups (p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann–Whitney U = 86; p < 0.05), a finding significantly driven by disease (t₍₁₇₎ = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations (n = 12) between the expression of several adenosine pathway components (p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the “mild” clinical dementia rating (CDR) bin compared with males in the “none” CDR bin (F_{(2, 13)} = 5.212; p < 0.05). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects (p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia’s pathology.

Introduction: The mammalian stress response relies on tightly regulated HPA axis signaling, and disruptions in glucocorticoid feedback are implicated in stress-related disorders such as PTSD. Although many individuals experience trauma, only some develop pathology, suggesting that individual differences in glucocorticoid responsivity may help predict susceptibility or resilience. Here, we examined whether corticosterone (CORT) responses to a mild stressor predict behavioral outcomes following single-prolonged stress (SPS) in male and female rats. Methods: Mild stress reactivity was quantified using area-under-the-curve (AUC) CORT responses to light-dark box exposure, after which animals underwent SPS, behavioral assays, and post-reinstatement cFos immunohistochemical analysis. Results: Females exhibited SPS-induced reductions in basal AM CORT and displayed a robust traumatic stress-related phenotype in which high CORT responders displayed increased anxiety-like behavior, impaired fear extinction, and enhanced reinstatement. Correlational and permutation analyses revealed a consistent pattern in SPS-exposed females in which lower pre-stress basal AM CORT and higher mild stress-induced CORT (AUC) predicted increased fear expression, indicating a dissociation between resting and stress-evoked glucocorticoid signals. In males, mild stress reactivity did not predict SPS-related outcomes; however, reduced pre-stress basal AM CORT in control males predicted increased fear expression, suggesting sex-specific differences in the potential predictive value of CORT dynamics. SPS and CORT responder status also differentially modulated cFos expression across stress-related brain regions, including the PVN, infralimbic cortex, and amygdala in both males and females. Conclusion: These findings demonstrate that mild stress reactivity and basal glucocorticoid dynamics can predict trauma-related phenotypes in a sex-specific manner, identifying them as a potential biomarker of PTSD susceptibility in females.