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Expression 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, which in humans are 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 can be 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 rhesus macaque layer III SGC and dlPFC. We found a larger population of extrasynaptic NMDAR-GluN2B in dendrites 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 neurodegenerative forces. 

Abstract Alzheimer’s disease cortical tau pathology initiates in the layer II cell clusters of entorhinal cortex, but it is not known why these specific neurons are so vulnerable. Aging macaques exhibit the same qualitative pattern of tau pathology as humans, including initial pathology in layer II entorhinal cortex clusters, and thus can inform etiological factors driving selective vulnerability. Macaque data have already shown that susceptible neurons in dorsolateral prefrontal cortex express a “signature of flexibility” near glutamate synapses on spines, where cAMP-PKA magnification of calcium signaling opens nearby potassium and hyperpolarization-activated cyclic nucleotide-gated channels to dynamically alter synapse strength. This process is regulated by PDE4A/D, mGluR3, and calbindin, to prevent toxic calcium actions; regulatory actions that are lost with age/inflammation, leading to tau phosphorylation. The current study examined whether a similar “signature of flexibility” expresses in layer II entorhinal cortex, investigating the localization of PDE4D, mGluR3, and HCN1 channels. Results showed a similar pattern to dorsolateral prefrontal cortex, with PDE4D and mGluR3 positioned to regulate internal calcium release near glutamate synapses, and HCN1 channels concentrated on spines. As layer II entorhinal cortex stellate cells do not express calbindin, even when young, they may be particularly vulnerable to magnified calcium actions and ensuing tau pathology.