NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders

Abstract

The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low “antidepressant” doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, “brain fog” in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a “foot in the door” to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent.

High-order brain interactions in ketamine during rest and task: A double-blinded cross-over design using portable EEG

“…The shifts in brain dynamics, speci cally an increase in redundancy, are most pronounced in alpha (echoing previous reports focused on this band, tasks and rest [46][47][48] ). Such alterations, particularly in the resting state, support the potential of ketamine to decrease top-down control and increase the sensitization to bottom-up signals 1,2,[12][13][14][15] . This phenomenon is manifested by an upswing in redundancy within brain dynamics, possibly re ecting a reduced top-down inhibition and an ampli cation of lower hierarchies of sensory information [12][13][14][15] .…”

Gender differences in major depressive disorders: A resting state fMRI study

“…DLPFC is an important part of PFC that thought to be associated with “cognitive” or “executive” functions ( 47 ), receiving input from specific sensory cortices, and regulate emotion through projections to the medial PFC and cingulate cortices ( 48 ). Recent studies have found that the imbalance in DLPFC activity may contribute to depression ( 49 , 50 ).…”

Targeting NMDA Receptor Complex in Management of Epilepsy

“…In addition, the NMDAR complex is involved in spatial learning [ 17 ]. Furthermore, NMDAR transmission is involved in persistent neuronal firing, which has been implicated in underlying neurocognitive disorders and particularly in aversive mental states [ 18 ].…”