Dysregulation of Astrocytic ATP/Adenosine Release in the Hippocampus Cause Cognitive and Affective Disorders: Molecular Mechanisms, Diagnosis, and Therapy

Abstract

The gliotransmitter adenosine 5'-triphosphate (ATP) and its enzymatic degradation product adenosine play a major role in orchestrating in the hippocampus cognitive and affective functions via P2 purinoceptors (P2X, P2Y) and P1 adenosine receptors (A1, A2A). Although numerous reviews exist on purinoceptors that modulate these functions, there is an apparent gap relating to the involvement of astrocyte-derived extracellular ATP. Our review focuses on the following issues: An impeded release of ATP from hippocampal astrocytes through vesicular mechanisms or connexin hemichannels and pannexin channels interferes with spatial working memory in rodents. The pharmacological blockade of P2Y1 receptors (P2Y1Rs) reverses the deficits in learning/memory performance in mouse models of familial Alzheimer's disease (AD). Similarly, in mouse models of major depressive disorder (MDD), based on acute or chronic stress-induced development of depressive-like behavior, a reduced exocytotic/channel-mediated ATP release from hippocampal astrocytes results in the deterioration of these behavioral responses. However, on the opposite, the increased stimulation of the microglial/astrocytic P2X7R-channel by ATP causes neuroinflammation and in consequence depressive-like behavior. In conclusion, there is strong evidence for the assumption that gliotransmitter ATP is intimately involved in the pathophysiology of cognitive and affective neuron/astrocyte-based human illnesses opening new diagnostic and therapeutic vistas for AD and MDD.