NMDA Receptors in Astroglia: Chronology, Controversies, and Contradictions from a Complex Molecule

Abstract

The neurocentric theory dismissed for decades the role of glia in information handling within the central nervous system (CNS). Nevertheless, almost 3 decades ago, this started to change and today astrocytes are considered relevant players for this function. Astrocytes "listen" to neuronal communication, regulate it, and respond at the cellular and synctitial level. Ionotropic glutamate NMDA receptor (NMDAR) is critical in CNS. It mediates synaptic neuronal communication and it is involved in different mechanisms. However, NMDAR is also expressed by astrocytes, but its functional role in these cells has not been deeply investigated and has been a matter of debate in the last decades. In this chapter, we briefly outline NMDAR intracellular transduction pathways initiated by Ca 2+ flux. Then, we review chronologically NMDAR expression and function in astrocytes that have been a source of controversies and apparent contradictions. Finally, some insights are presented regarding NMDAR in astrocytes in the context of the tripartite synapse concept and the recently described Ca 2+ fluxindependent metabotropic-like NMDAR function in astrocytes. Given the complex molecular nature of NMDAR, its critical role, and the relevance of astrocytes, the study of astrocytic NMDAR promises to provide further understanding of CNS physiology and pathology.

NMDAR in cultured astrocytes: Flux‐independent pH sensor and flux‐dependent regulator of mitochondria and plasma membrane‐mitochondria bridging

“…12,28 More importantly, proton concentration has been found critical for NMDAR flux inhibition [15][16][17] and, 1mM NMDA has been previously found to regulate astrocyte and neuronal functions. 5,18,19 As shown in Figure 1A (left column), the maximal averaged response was observed with NMDA/pH6 (∫(ΔF/F 0 ) = 5.49) (The averaged response is that obtained averaging ΔF/F 0 responses from all experiments and cells tested in the same condition). In contrast, NMDA/pH7 only slowly and slightly increased iCa 2+ (∫(ΔF/F 0 ) = 2.81), whereas NMDA/pH5 also increased iCa 2+ (∫(ΔF/F 0 ) = 3.37), but to a lesser extent than NMDA/ pH6.…”

“…[15][16][17] Moreover, the NMDA concentration used here has been found by us and others to regulate astrocyte and specific neuronal functions. 5,18,19 In our previous work, we also demonstrated that intracellular Ca 2+ (iCa 2+ ) rise was sensitive to competitive NMDAR inhibitors or GluN1 subunit Knock Down, demonstrating NMDAR involvement. Surprisingly, iCa 2+ rise was insensitive to NMDAR pore blocker MK-801 or extracellular Ca 2+ depletion, but it was blocked by InsP 3 R and RyR inhibitors.…”

“…0.4 with the Spinning Disc microscope described above with a 561 Laser for excitation and an emission filter of 605/52 nm. For labeling rCCA with DISC 3 (5), cells were labeled with 10 µM DISC 3 (5) for 10 minutes at 37°C in HBSS. Then cells were washed and recorded (at 0.5 Hz) with the Spinning Disc microscope described above with a 561 (BCECF) or 640 (DISC 3 (5)) Laser for excitation and an emission filter of 605/52 (BCECF) or 700/75 nm (DISC 3 (5)).…”

“…However, nowadays it is clear that astrocytes in situ express functional NMDAR, although it displays several singularities, given in part by its subunit composition. 5,6 Nevertheless, in cultured astrocytes, classical electrophysiological experiments found no evidence of ionic flux, and controversial findings have questioned NMDAR function. 5,7 Nonetheless, we and others have recently demonstrated that the NMDAR can signal in a flux-independent manner.…”

“…5,6 Nevertheless, in cultured astrocytes, classical electrophysiological experiments found no evidence of ionic flux, and controversial findings have questioned NMDAR function. 5,7 Nonetheless, we and others have recently demonstrated that the NMDAR can signal in a flux-independent manner. [8][9][10] In these cells, we found NMDAR subunit expression by RT-PCR and immunofluorescence, Ca 2+ release from the Endoplasmic Reticulum (ER) and mitochondrial membrane potential (mΔΨ) depletion in response to NMDA 1mM at pH≈6 (NMDA/pH6).…”