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.

Keywords: NMDAR (NMDA receptor); cingulate cortex; depression; prefrontal cortex; working memory.

Figure 1

Primate cortical circuits. (A) Schematic diagram of circuits in the rhesus monkey cortex, where the lateral surface represents the outer world, and the medial and orbital surface represents inner state. The dorsal stream is shown on the lateral surface, where dlPFC represents visual space in working memory, and generates the goals for top-down regulation of emotion. The medial surface shows the pathways mediating the emotional response to pain, arising from medial thalamic projections to the insular cortex (not shown) and the anterior cingulate cortex BA24, which both project to BA25 (subgenual cingulate). BA25 is a major center for visceromotor outputs, e.g., to the amygdala, brainstem, and hypothalamus to alter heart rate. These cingulate cortices are often overactive in depression, and a target of DBS treatments. The dlPFC provides top-down regulation of emotion through indirect projections to BA25 via areas BA10m and BA32, and direct projections to BA24 (not shown). (B) The increasing timescales across the primate cortical hierarchy, and their relationship to GRIN2B expression. Based on (11) and (9). LIP, lateral intraparietal cortex; MT, middle temporal visual cortex.

Figure 2

The persistent firing of dlPFC Delay cells depends on NMDAR with GluN2B subunits. (A) Schematic illustration of the recurrent excitatory microcircuits in deep layer III of dlPFC that generate persistent firing. (B) A dlPFC Delay cell that represents the spatial position of 270° during a spatial working memory task, maintaining firing across the delay period for only that preferred location. Iontophoresis of the selective NMDAR- GluN2B antagonist, TCN237, completely blocks the ability of the neuron to generate representations of visual space.

Figure 3

The primate dlPFC and primary visual cortex (V1) have very different neurotransmission. (A) The dlPFC depends on NMDAR neurotransmission, including those with slowly closing GluN2B subunits, that are exclusively within the PSD. The permissive excitatory effects to relieve the magnesium (Mg²⁺) block of the NMDAR ion channel are provided by acetylcholine (including Nic-a7R), with a surprisingly small influence from AMPAR. (B) Iontophoresis of the AMPAR antagonist, CNQX, has only subtle effects on dlPFC Delay cell firing, while blockade of NMDAR- GluN2B with Ro25-6981 (Ro) markedly reduces Delay cell firing. (C) Neurons in primate V1 show a more classic profile, relying heavily on AMPAR neurotransmission, with less influence by NMDAR. (D) Iontophoresis of low doses of the AMPAR antagonist, CNQX, markedly reduces V1 neuronal firing, while blockade of NMDAR- GluN2B with Ro has little effect. Adapted from (9) and (8). *p < 0.05, ***p < 0.001.

Figure 4

Hypothesis regarding the state of cortical circuits under conditions of health vs. depression, and their normalization by antidepressant treatments. (A) Under healthy conditions, the dlPFC and rostral medial PFC areas provide top-down regulation of the cingulate cortices via medial PFC connections, reducing BA25 activation of the stress response. The dlPFC also projects directly to the monoamine nuclei in the brainstem to regulate catecholamine release. (B) Under conditions of stress or depression, elevated activity in the cingulate cortices can activate the amygdala, and very high levels of catecholamine release in cortex takes higher PFC areas such as dlPFC “offline.” Thus, there is a self-perpetuating, unregulated state, where primitive circuits prevail. (C) Many antidepressant treatments reduce the activity of BA25. This may give the cortex a “foot in the door” to restore top-down regulation, especially when treatments promote dendritic spine restoration in higher PFC circuits. Other treatments may directly enhance the top-down regulation by the left dlPFC, e.g., rTMS and insight therapies.