Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems

Abstract

Glutamate is the main excitatory neurotransmitter of the central nervous system (CNS), released both from neurons and glial cells. Acting via ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate receptors, it is critically involved in essential regulatory functions. Disturbances of glutamatergic neurotransmission can be detected in cognitive and neurodegenerative disorders. This paper summarizes the present knowledge on the modulation of glutamate-mediated responses in the CNS. Emphasis will be put on NMDA receptor channels, which are essential executive and integrative elements of the glutamatergic system. This receptor is crucial for proper functioning of neuronal circuits; its hypofunction or overactivation can result in neuronal disturbances and neurotoxicity. Somewhat surprisingly, NMDA receptors are not widely targeted by pharmacotherapy in clinics; their robust activation or inhibition seems to be desirable only in exceptional cases. However, their fine-tuning might provide a promising manipulation to optimize the activity of the glutamatergic system and to restore proper CNS function. This orchestration utilizes several neuromodulators. Besides the classical ones such as dopamine, novel candidates emerged in the last two decades. The purinergic system is a promising possibility to optimize the activity of the glutamatergic system. It exerts not only direct and indirect influences on NMDA receptors but, by modulating glutamatergic transmission, also plays an important role in glia-neuron communication. These purinergic functions will be illustrated mostly by depicting the modulatory role of the purinergic system on glutamatergic transmission in the prefrontal cortex, a CNS area important for attention, memory and learning.

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…NMDA is the receptor which is present on the postsynaptic membrane of the neuron. The action of this receptor is modulated by the glutamate neurotransmitter [45–47]. Revett et al have shown there is an increased presynaptic release of glutamate and there is a failure in re-uptake of released glutamate, which in turn leads to a tonic activation of NMDA receptors, and thus contributes to an excess in AD [48].…”

Adenosine A1 Receptor mRNA Expression by Neurons and Glia in the Auditory Forebrain

“…Second, glia and neuron-glia interactions are involved in a vast array of brain functions that often involve adenosine signaling (Stevens et al, 2002;Fields and Burnstock, 2006;Boison, 2008a;Pelligrino et al, 2011;Lovatt et al, 2012;Del Puerto et al, 2013;Domercq et al, 2013;Bynoe et al, 2015;Coppi et al, 2015;Koles et al, 2016). Whether Adora1 expression is restricted to specific neuronal and glial subpopulations or subdivisions of the auditory forebrain is unknown, but this knowledge is essential for the understanding and modeling of adenosine signaling in forebrain circuits.…”

“…Adenosine plays important roles in the modulation of neuronal activity and neuro-glial interactions in the brain (Burnstock, 2007;Boison, 2008a;Abbracchio et al, 2009;Housley et al, 2009;Koles et al, 2016). Multiple sources of extracellular adenosine have been identified, and their respective contributions in this complex system continue to be studied.…”

“…In the peripheral and central nervous systems, purinergic signaling is a widespread mechanism for communication between neurons, glia, and vascular cells. Purines such as adenosine and adenosine triphosphate (ATP) can function as neurotransmitters, co‐transmitters, neuromodulators, and as signals in neuro–glial interactions (Burnstock, ; Boison, ; Abbracchio et al, ; Housley et al, ; Koles et al, ). Accordingly, their functional impact on the nervous system is broad, including key roles in development, behavior, regeneration, plasticity, and pathology (Dale, ; Burnstock et al, ; Wei et al, ; Zimmermann, ; Del Puerto et al, ; Dias et al, ; Sebastiao and Ribeiro, ; Krugel, ; Pedata et al, ).…”

“…In the brain, ATP and adenosine are released in an activity dependent manner from the presynaptic terminals of neurons by vesicle‐mediated exocytosis, postsynaptic membranes (dendrites), and axons (Fredholm et al, ; Wall and Dale, ; Abbracchio et al, ; Burnstock et al, ; Cunha, ). They may also be released by glia, especially astrocytes, via vesicular secretion, transport proteins, and membrane channels (Boison et al, ; Koles et al, ).…”