Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

Abstract

Schizophrenia (SZ) is a major chronic neuropsychiatric disorder characterized by a hyperdopaminergic state. The hypoadenosinergic hypothesis proposes that reduced extracellular adenosine levels contribute to dopamine D 2 receptor hyperactivity. ATP, through the action of ecto-nucleotidases, constitutes a main source of extracellular adenosine. In the present study, we examined the activity of ecto-nucleotidases (NTPDases, ecto-5′-nucleotidase, and alkaline phosphatase) in the postmortem putamen of SZ patients (n=13) compared with aged-matched controls (n=10). We firstly demonstrated, by means of artificial postmortem delay experiments, that ectonucleotidase activity in human brains was stable up to 24 h, indicating the reliability of this tissue for these enzyme determinations. Remarkably, NTPDase-attributable activity (both ATPase and ADPase) was found to be reduced in SZ patients, while ecto-5′-nucleotidase and alkaline phosphatase activity remained unchanged. In the present study, we also describe the localization of these ecto-enzymes in human putamen control samples, showing differential expression in blood vessels, neurons, and glial cells. In conclusion, reduced striatal NTPDase activity may contribute to the pathophysiology of SZ, and it represents a potential mechanism of adenosine signalling impairment in this illness.

A2A‐D2 receptor–receptor interaction modulates gliotransmitter release from striatal astrocyte processes

“…Actually, reduced striatal ecto‐nucleotidase activity in schizophrenia patients supports the ‘hypo‐adenosinergic hypothesis’ (Aliagas et al . ), as catabolism of extracellular ATP or AMP by ecto‐nucleotidases near A2A receptors seems related to the activation of the receptors (Augusto et al . ).…”

“…In fact, adenosine's crucial roles in synaptic/non-synaptic transmission in basal ganglia are recognized (see Sperl agh and Vizi 2011). Actually, reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the 'hypo-adenosinergic hypothesis' (Aliagas et al 2013), as catabolism of extracellular ATP or AMP by ecto-nucleotidases near A2A receptors seems related to the activation of the receptors . In agreement with such a view, it has been demonstrated that the ecto-nucleotidases involved in adenosine formation in proximity of A2A receptors are abundant in striatal gliosomes , consistent with the involvement of glial A2A receptors in the disease pathophysiology (see also Rial et al 2014).…”

Alterations of Astrocytes in the Context of Schizophrenic Dementia

“…Striatal astrocytes express the heterodimer native receptors A2A-D2 (Cervetto et al, 2017). D2 receptors inhibit presynaptic glutamate release, while A2A receptor activation eliminates the effect of D2 receptor activation (Aliagas et al, 2013). A study was carried out using a synthetic peptide VLRRRRRKRVN, corresponding to the receptor region involved in the electrostatic interaction between A2A and D2 receptors.…”

Comorbidities in Neurology: Is adenosine the common link?

“…A link between ADO hypofunction and SZ is supported by clinical evidence demonstrating increased enzymatic degradation of adenosine in SZ patients (Brunstein et al, 2007; Dutra et al, 2010). Most recently, reduced striatal ecto-nucleotidase (adenosine producing enzyme) activity was found in schizophrenia patients (Aliagas et al, 2013). A meta-analysis of six randomized controlled trials comparing adenosine modulators with placebo as adjuvant therapy in patients with schizophrenia demonstrated benefits in overall psychopathology (especially positive symptoms) in schizophrenia (Hirota and Kishi, 2013).…”