ATP indirectly stimulates hippocampal CA1 and CA3 pyramidal neurons via the activation of neighboring P2X7 receptor-bearing astrocytes and NG2 glial cells, respectively

Abstract

There is ongoing dispute on the question whether CNS neurons possess ATP-sensitive P2X7 receptors (Rs) or whether only non-neuronal cells bear this receptor-type and indirectly signal to the neighboring neurons. We genetically deleted P2X7Rs specifically in astrocytes, oligodendrocytes and microglia, and then recorded current responses in neurons to the prototypic agonist of this receptor, dibenzoyl-ATP (Bz-ATP). These experiments were made in brain slice preparations taken from the indicated variants of the P2X7R KO animals. In hippocampal CA3, but not CA1 pyramidal neurons, the deletion of oligodendrocytic (NG2 glial) P2X7Rs abolished the Bz-ATP-induced current responses. In contrast to the Bz-ATP-induced currents in CA3 pyramidal neurons, current amplitudes evoked by the ionotropic glutamate/GABAAR agonists AMPA/muscimol were not inhibited at all. Whereas in the CA3 area NG2 glia appeared to mediate the P2X7R-mediated stimulation of pyramidal neurons, in the CA1 area, astrocytic P2X7Rs had a somewhat similar effect. This was shown by recording the frequencies and amplitudes of spontaneous excitatory currents (sPSCs) in brain slice preparations. Bz-ATP increased the sPSC frequency in CA1, but not CA3 pyramidal neurons without altering the amplitude, indicating a P2X7R-mediated increase of the neuronal input. Micro-injection of the selective astrocytic toxin L-α-aminoadipate into both hippocampi, or the in vitro application of the GABAAR antagonistic gabazine, completely blocked the frequency increases of sPSCs. Hence, CA1 and CA3 pyramidal neurons of the mouse did not possess P2X7Rs, but were indirectly modulated by astrocytic and oligodendrocytic P2X7Rs, respectively.

P2X7 purinergic receptor modulates dentate gyrus excitatory neurotransmission and alleviates schizophrenia-like symptoms in mouse

“…It is well-known that extracellular calcium in physiological concentrations acts as a negative allosteric modulator of P2X7R by reducing the affinity of receptors for orthosteric ligand agonists. 49 , 50 Thus, although a low Ca 2+ (0.5 mM)/0 Mg 2+ ACSF is routinely used to investigate the electrophysiological role of P2X7Rs in brain slices, 11 , 51 the physiological calcium concentration is typically around 1.3 mM and varies from 1.3 mM to 1.8 mM (normally below 1.8 mM) depending on arousal/sleep or other situations. 52 , 53 , 54 Therefore, in our study, we utilized both 1.3 mM Ca 2+ /2 mM Mg 2+ containing physiological ACSF and low Ca 2+ (0.5 mM)/0 Mg 2+ ACSF and found that BzATP was able to induce P2X7R-mediated response in both cases.…”

Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

“…The P2X7 receptor was in fact first cloned from a rat brain tissue cDNA library, 21 and its expression and role in the CNS have been extensively researched. The expression of the P2X7 receptor in glial cells is widely accepted, whereas its expression in neurons has been a topic of heated debate, 50–52 which remains unsettled 53–55 . The P2X7 receptor serves an important mechanism mediating the communications between neurons and glia 56 .…”

“…The expression of the P2X7 receptor in glial cells is widely accepted, whereas its expression in neurons has been a topic of heated debate, 50 , 51 , 52 which remains unsettled. 53 , 54 , 55 The P2X7 receptor serves an important mechanism mediating the communications between neurons and glia. 56 The P2X7 receptor in microglia also acts as the PRR for ATP released from degenerating and stressed cells, and the ATP‐P2X7 receptor signaling axis plays a critical role in microglial activation and neuroinflammation in the pathogenesis and development of multiple neurodegenerative diseases and psychological disorders.…”