Altered purinergic receptor expression in the frontal cortex in schizophrenia

Abstract

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.

Extracellular ATP inhibits excitatory synaptic input on parvalbumin positive interneurons and attenuates gamma oscillations via P2X4 receptors

“…For example, Aβ was shown to increase the number of P2X4 receptors in the cell membrane of primary hippocampal neurons by decreasing their internalization (Varma et al, 2009). In a recent work, increased P2X4 receptor mRNA expression was found in the prefrontal cortex of schizophrenia patients (Alnafisah et al, 2022). These data suggest that P2X4 receptor mediated effects on network activity might be stronger in different brain pathologies compared with physiological conditions.…”

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

“…Depending upon the nature of the interfering agent, exact gestational timing, insult's duration and/or intensity and the preferential involvement of specific brain areas, the offspring may develop diverse clinical manifestations, ranging from mild-to-serious cognitive impairment, altered social behavior, distinct sensorimotor neurological defects and alterations of specific purinergic pathways or receptors. • Increased in the dorsolateral prefrontal cortex of schizophrenic subjects [43] • Involved in the appearance of schizophrenia-like behaviors and in impairments in dendritic outgrowth in hippocampal neurons in the MIA model [68] Rett syndrome (RTT)…”

“…In addition, P2X7, P2X4 and P2X5 mRNA expression was significantly increased in the dorsolateral prefrontal cortex of subjects diagnosed with SCZ compared to matched, non-psychiatrically ill controls. P2X7 was also significantly increased at protein levels [43].…”