Biology subjects

Arnsten, A. F.

Publications and source records attributed to Arnsten, A. F..

6 recordsLinked to original sources

bioRxiv2025

Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease

Sporadic Alzheimers disease (sAD) lacks effective preventive therapies, underscoring the need to target pathogenic drivers. Aberrant calcium signaling is an established early event in sAD pathogenesis that is closely linked to neuroinflammation. Aged rhesus macaques are predominantly APOE-{varepsilon}4 homozygotes and naturally exhibit cognitive decline, calcium dysregulation, amyloid deposition, and tau pathology, which allows for a translationally relevant animal model. We previously identified an evolutionarily expanded role for postsynaptic type 3 metabotropic glutamate receptors (mGluR3) in dorsolateral prefrontal and entorhinal cortex, where they regulate cAMP- calcium opening of K channels to sustain neuronal firing and working memory. mGluR3 signaling is driven by N-acetylaspartylglutamate (NAAG) and constrained by glutamate carboxypeptidase II (GCPII), whose expression rises with age and inflammation. In prior work, chronic inhibition of GCPII with the orally bioavailable inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) improved neuronal firing, working memory, and reduced pT217Tau pathology in aged macaques. Here, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to define the proteomic consequences of chronic 2-MPPA treatment in vulnerable (entorhinal cortex, dorsolateral prefrontal cortex) versus resilient (primary visual cortex) regions. We identified >2,400 proteins across experimental conditions, and label-free quantification revealed region-specific differential expression patterns paralleling known vulnerability gradients in sAD. Gene ontology enrichment of vulnerable regions implicated pathways governing protein deneddylation, amyloid and tau-associated processes, synaptic plasticity, mitochondrial homeostasis, and oxidative stress, revealing putative targets for therapeutic intervention in sAD. These findings demonstrate that GCPII inhibition engages distinct, region-selective molecular programs in the aging primate cortex, consistent with the protection of circuits most vulnerable to sAD. By mapping the proteomic shifts that occur with treatment, we reveal molecular signatures that not only serve as candidate biomarkers but also highlight novel mechanistic pathways contributing to calcium-driven degeneration in sAD. As such, more focused investigations into these pathways of therapeutic interest are warranted, in addition to the analysis of key post-translational modifications and their potential roles in sAD.

neuroscience↗

bioRxiv2025

Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

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 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 Alzheimers 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 Alzheimers disease, and may help to explain how rapid acting antidepressants exert therapeutic action across diverse neural circuits.

neuroscience↗

bioRxiv2024

Single neuron diversity supports area functional specialization along the visual cortical pathways

Humans and other primates have specialized visual pathways composed of interconnected cortical areas. The input area V1 contains neurons that encode basic visual features, whereas downstream in the lateral prefrontal cortex (LPFC) neurons acquire tuning for novel complex feature associations. It has been assumed that each cortical area is composed of repeatable neuronal subtypes, and variations in synaptic strength and connectivity patterns underlie functional specialization. Here we test the hypothesis that diversity in the intrinsic make-up of single neurons contributes to area specialization along the visual pathways. We measured morphological and electrophysiological properties of single neurons in areas V1 and LPFC of marmosets. Excitatory neurons in LPFC were larger, less excitable, and fired broader spikes than V1 neurons. Some inhibitory fast spiking interneurons in the LPFC had longer axons and fired spikes with longer latencies and a more depolarized action potential trough than in V1. Intrinsic bursting was found in subpopulations of both excitatory and inhibitory LPFC but not V1 neurons. The latter may favour temporal summation of spikes and therefore enhanced synaptic plasticity in LPFC relative to V1. Our results show that specialization within the primate visual system permeates the most basic processing level, the single neuron.

neuroscience↗

bioRxiv2024

Dopamine D1 receptor expression in dlPFC inhibitory parvalbumin neurons may contribute to higher visuospatial distractibility in marmosets versus macaques

Marmosets and macaques are common non-human primate models of cognition, yet marmosets appear more distractible and perform worse in cognitive tasks. The dorsolateral prefrontal cortex (dlPFC) is pivotal for sustained attention, and prior macaque research suggests that dopaminergic modulation and inhibitory parvalbumin (PV) neurons could contribute to distractibility. Thus, we compared the two species using a visual fixation task with distractors, performed molecular and anatomical analyses in dlPFC, and linked functional microcircuitry with cognitive performance using computational modeling. We found that marmosets are more distractible than macaques, and that marmoset dlPFC PV neurons contain higher levels of dopamine-1 receptor (D1R) transcripts and protein, similar to their levels in mice. The modeling indicated that higher D1R expression in marmoset dlPFC PV neurons may increase distractibility by making dlPFC microcircuits more vulnerable to disruptions of their task-related persistent activity, especially when dopamine is released in dlPFC in response to unexpected salient stimuli. Declaration of InterestsThe authors have nothing to declare. Author ContributionsAFTA, MKPJ, TGI, and SFW designed the study; MKPJ collected and analyzed anatomical data; TGI designed the computational framework with guidance from RG and SFW; TGI performed the modeling simulations and data analysis; FM and SAM collected and analyzed transcriptomics data; GGB and DAL provided macaque brain tissue for transcriptomics performed by FM; SM and NS collected and analyzed phylogenetic transcriptomics dataset; JFM and ASN performed and analyzed the behavioral testing; IW and JMT provided the marmoset tissue for immunofluorescence; MKPJ, TGI, SFW, and AFTA wrote the first draft and all authors revised and edited subsequent drafts of the article.

neuroscience↗

bioRxiv2024

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimers disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and 7-nicotinic receptors (nic-7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

neuroscience↗

bioRxiv2023

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration

Structured Abstract INTRODUCTIONpT217-tau is a novel fluid-based biomarker that predicts onset of Alzheimers disease (AD) symptoms, but little is known about how pT217-tau arises in brain, as soluble pT217-tau is dephosphorylated postmortem in humans. METHODSWe utilized multi-label immunofluorescence and immunoelectron-microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally-occurring tau pathology and assayed pT217-tau levels in plasma. RESULTSpT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to CSF/blood. Plasma pT217-tau levels increased across the age-span and thus can serve as a biomarker in macaques. DISCUSSIONThese data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.

neuroscience↗