NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex

Abstract

Summary Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPAR) contributed background depolarization to sustain network firing. In contrast, many Response cells -which likely predominate in rodent PFC- were sensitive to AMPAR blockade and increased firing following systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s Disease profoundly impair cognition.

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

“…Interestingly, NR2B blockade of the dlPFC neurons studied by Wang et al (2013) is not likely to be responsible for the deficits in DMS performance in the current studies. Lesions of medial but not dorsolateral PFC have been shown to impair DMS performance (Bachevalier and Mishkin, 1986;Passingham, 1975).…”

“…Patients with frontal lobe lesions were not impaired on the CANTAB DMS task, although frontal patients were impaired on the vsPAL (Owen et al, 1995). Therefore, dlPFC neurons, such as those studied by Wang et al, (2013) may be involved in the spatial memory components of vsPAL; however, the DMS impairment implicates regions outside of the dlPFC. Performance in both vsPAL and DMS tasks is similarly sensitive to function in temporal cortical and hippocampal structures, as well as medial PFC structures, suggesting their involvement in the cognitive impairment observed in the present studies.…”

“…In nonhuman primates there are no published reports describing the impact of systemic NR2B NAM treatment on cognition. Local injection of Ro25-6981 into the dorsolateral prefrontal cortex (dlPFC) of macaques attenuates firing of neurons active during the delay period of a working memory task; however, the impact on task accuracy was not reported and systemic dosing of an NR2B NAM was not examined (Wang et al, 2013). Thus, although these electrophysiological results suggest that NR2B NAMs may impair working memory in nonhuman primates, direct demonstration of cognitive impairment has not yet been shown.…”

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…It is not known at present whether the lack effects of CP-101,606 on gamma power in rats translates to humans. In fact, there may be subtle but important differences in the distribution of NR2B subunit containing receptors between rat and non-human primate, as suggested by Arnsten and colleagues (Wang et al, 2013) that could result in a lack of translation on some functional measures. Thus, it will be important to determine the neurophysiological signature of NR2B NAMs in humans and non-human primates to further clarify the role of gamma disruption in the psychotomimetic effects of NMDA receptor inhibition.…”

Alterations in High-Frequency Neuronal Oscillations in a Cynomolgus Macaque Test of Sustained Attention Following NMDA Receptor Antagonism

“…In our study, the effect on 'high' gamma following PCP administration is consistent with EEG and magnetoencephalography results reported in healthy volunteers receiving acute ketamine (Hong et al, 2010;Rivolta et al, 2015), as well as with in vivo local field potentials and EEG recordings following the administration of NMDA receptor antagonists to rodents (Ehrlichman et al, 2009;Pinault, 2008;Lazarewicz et al, 2010;Sullivan et al, 2015). The enhancement in gamma oscillations following acute NMDA receptor inhibition could result from at least two separate mechanisms in which the NMDA receptor antagonist: (i) acts directly on PV-containing GABAergic interneurons and thereby disinhibits pyramidal cells (eg, layer 5 of dlPFC); or (ii) acts directly on pyramidal cells causing a reduction in glutamate release which in turn reduces the stimulation of AMPA receptors on GABAergic interneurons which may also transiently disinhibit pyramidal cells for example in layer 3 of dlPFC (Rotaru et al, 2011;Wang et al, 2013). Both mechanisms could increase extracellular glutamate release and enhance gamma oscillations, leading to schizophrenia-like symptoms in humans and animals (Krystal et al, 1994;Moghaddam et al, 1997).…”