Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices
Authors: Joyce MKP , Datta D , Arellano J , Duque A , Morozov YM , Morrison JH , Arnsten AFT 
Published: February 2025

AbstractExpression of the N-methyl-D-aspartate receptor, particularly when containing the GluN2B subunit (NMDAR-GluN2B) varies across the prefrontal cortex (PFC). In humans, the subgenual cingulate cortex (SGC) contains among the highest levels of NMDAR-GluN2B expression, while the dorsolateral prefrontal cortex (dlPFC) exhibits a more moderate level of NMDAR-GluN2B expression. NMDAR-GluN2B are commonly associated with ionotropic synaptic function and plasticity, and are essential to the neurotransmission underlying working memory in the macaque dlPFC in the layer III circuits afflicted in schizophrenia. However, NMDAR-GluN2B can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked to neurodegenerative processes. The SGC is an early site of tau pathology in sporadic Alzheimer’s Disease (sAD), which mirrors its high NMDAR-GluN2B expression. Additionally, the SGC is hyperactive in depression, which is treated with NMDAR antagonists. Given the clinical relevance of NMDAR in the SGC and dlPFC, the current study used immunoelectron microscopy (immunoEM) to quantitatively compare the synaptic and extrasynaptic expression patterns of NMDAR-GluN2B across excitatory and inhibitory neuron dendrites in the rhesus macaque SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendritic shafts and spines of putative pyramidal neurons in SGC as compared to the dlPFC, while the dlPFC had a higher proportion of synaptic NMDAR-GluN2B. In contrast, in putative inhibitory dendrites from both areas, extrasynaptic expression of NMDAR-GluN2B was far more frequently observed over synaptic expression. These findings may provide insight into varying cortical vulnerability to alterations in excitability and to neurodegenerative forces.Scope StatementNMDAR are ionotropic receptors that contribute to neurotransmission and second messenger signaling events. NMDAR can induce a diverse array of neuronal events, in part due to variation in subunit composition and subcellular localization of receptor expression. Expression of the GluN2B subunit varies across the prefrontal cortex in humans. This subunit is highly expressed in the subgenual cingulate, an area associated with mood and emotion, and more moderately expressed in the dorsolateral prefrontal cortex, an area associated with cognitive processes. Extrasynaptic NMDAR, which often contain with the GluN2B subunit, have been linked to detrimental cellular events like neurodegeneration. Here, using high resolution electron microscopy in rhesus macaques, we found evidence that extrasynaptic NMDAR-GluN2B expression may be more prominent in subgenual cortex than in the dorsolateral prefrontal cortex. Conversely, synaptic NMDAR-GluN2B may be more prominent in the dorsolateral prefrontal cortex, consistent with their essential contribution to neuronal firing during working memory. These findings may help to illuminate the propensity of the subgenual cortex to tonic hyperactivity in major depression and its vulnerability to neurodegeneration in Alzheimer’s disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.