P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

Abstract

ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.

The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

“…Thus, multiple ATP release sites exist in the normal brain [72]. ATP acts as a neurotransmitter and is released during synaptic transmission [73]. Astrocytes release ATP and thereby generate Ca 2+ waves as a propagating signal [74].…”

Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy

“…Proconvulsive roles for P2Y 1 have been suggested by the observation that P2Y 1 receptor activation leads to enhanced Ca 2ϩ signaling and astroglial activation in experimental kindling, a model of epileptogenesis (Á lvarez-Ferradas et al, 2015). P2Y 1 has also been shown to regulate the release of different neurotransmitters in the brain, including glutamate, noradrenaline, and GABA, and to alter the sensitivity or availability of neurotransmitter receptors, including metabotropic glutamate receptor 1 (mGluR1), NMDA, gamma-aminobutyric acid (GABA A ), and P2X receptors (Guzman and Gerevich, 2016). A more recent study demonstrated that, although P2Y 1 antagonism had no effect on seizure severity, it significantly reduced seizureinduced neuronal loss in the hippocampus (Simoes et al, 2018).…”

The Role of Nucleotides in Glial Cells during Peripheral Nerve Trauma and Compressive Disorders

“…The P2Y2 and P2Y4 receptors activate phospholipase C, increasing the cytosolic Ca 2+ concentration from the intracellular reserves and the activation of protein kinase C in response to the production of inositol 1,4,5-trisphosphate and diacylglycerol, respectively [111]. Generally, P2Y receptors that increase intracellular Ca 2+ concentration induce the tricarboxylic acid cycle and increase ATP production, which promotes the maintenance of ion homeostasis and antioxidant defense [109].…”

“…P2Y2 receptors are expressed by neurons, astrocytes, and microglia and regulate actin polymerization and cytoskeletal rearrangements through the Rac/Rho pathways [112], as well as the P2Y4 receptors [113]. Its activation confers neuroprotection in several ways: the promotion of neurite outgrowth, increased cell motility, nonamyloidogenic processing of the amyloid precursor protein, and increased phagocytosis and degradation of the amyloid-beta peptide [102,111]. Moreover, studies have shown that microglia respond rapidly to nerve lesions by migrating to the spinal projection territories of the central terminals of injured primary afferents, with subsequent proliferation, activation of p38 MAPK and ERK1/2, and production of proinflammatory cytokines and chemokines [114].…”

“…The modulation exerted by activation of P2Y4 receptors is linked to the positive influence on excitatory transmission mediated by postsynaptic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, through increased glutamate release [111], while P2Y2 receptors modulation is linked to increased currents through the Ca 2+ permeable transient receptors potential vanoloyide 1 (TRPV1) in the PNS [115]. This high concentration of intracellular Ca 2+ can participate in responses through annexins-responsible for signal transduction, trafficking, and vesicle aggregation and membrane organization-that bind negatively charged phospholipids in a Ca 2+ -dependent way [116].…”