NMDA receptor mediated tonic excitatory currents are elicited by EAAT inhibition on human neocortical pyramidal...

Ambient glutamate is capable of regulating neural excitability and contributes to several brain pathologies. It is well established by experiments on rodent tissue that extrasynaptic glutamate -mainly regulated by astrocytic glutamate uptake- can elicit both phasic slow inward currents (SICs) and tonic inward currents. These currents are thought to be mediated by overlapping mechanisms and receptors; and exist under physiological conditions. SICs were also found in the human neocortex but the existence of the tonic inward currents and their relationship with SICs have not been demonstrated yet.

We aimed to investigate tonic inward currents and their relation to slow inward currents (SICs) elicited by the inhibition of glutamate transport in the human neocortex. Brain samples removed for accessing the primary brain tumors or metastases were collected from patients with broad age range. Slice electrophysiological approach and post-hoc morphological analysis was used.

We found that inhibition of the EAAT transporters by DL-TBOA elicited both SICs and tonic inward currents. The tonic current was only partially reverted by the GluN2B subunit specific NMDA receptor (NMDAR) antagonist ifenprodil, whereas SICs were almost fully eliminated. The amplitude of the current was inversely proportional with the age of the patient and disappeared in elderly over the age of 70. The charge transfer of SICs per minute was directly proportional with the magnitude of the tonic inward current. Omitting magnesium from the recording solution or application of the EAAT positive allosteric modulator GT949 did not elicit any notable tonic current.

In summary, NMDAR-dependent tonic inward currents are overlapping but partially separable phenomena from SICs. One might hypothesize that the tonic current is only present under excitotoxic conditions and do not determine physiological neuronal excitability in human.