The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP-synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with our observations of decreased integrity of oxidative phosphorylation supercomplexes and ATP-synthase dimers in WS. Thus, we identify DNAJC30 as an auxiliary component of ATP-synthase machinery and reveal mitochondrial maladies as underlying certain defects in brain development and function associated with WS.

Risky Business: The Circuits that Impact Stress-Induced Decision-Making.

How does stress promote risky decision-making? Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome.

The meso-connectomes of mouse, marmoset, and macaque: network organization and the emergence of higher cognition.

The recent publications of the inter-areal connectomes for mouse, marmoset, and macaque cortex have allowed deeper comparisons across rodent vs. primate cortical organization. In general, these show that the mouse has very widespread, "all-to-all" inter-areal connectivity (i.e. a "highly dense" connectome in a graph theoretical framework), while primates have a more modular organization. In this review, we highlight the relevance of these differences to function, including the example of primary visual cortex (V1) which, in the mouse, is interconnected with all other areas, therefore including other primary sensory and frontal areas. We argue that this dense inter-areal connectivity benefits multimodal associations, at the cost of reduced functional segregation. Conversely, primates have expanded cortices with a modular connectivity structure, where V1 is almost exclusively interconnected with other visual cortices, themselves organized in relatively segregated streams, and hierarchically higher cortical areas such as prefrontal cortex provide top-down regulation for specifying precise information for working memory storage and manipulation. Increased complexity in cytoarchitecture, connectivity, dendritic spine density, and receptor expression additionally reveal a sharper hierarchical organization in primate cortex. Together, we argue that these primate specializations permit separable deconstruction and selective reconstruction of representations, which is essential to higher cognition.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders.

Neuroinflammatory disorders preferentially impair the higher cognitive and executive functions of the prefrontal cortex (PFC). This includes such challenging disorders as delirium, perioperative neurocognitive disorder, and the sustained cognitive deficits from "long-COVID" or traumatic brain injury. There are no FDA-approved treatments for these symptoms; thus, understanding their etiology is important for generating therapeutic strategies. The current review describes the molecular rationale for why PFC circuits are especially vulnerable to inflammation, and how α2A-adrenoceptor (α2A-AR) actions throughout the nervous and immune systems can benefit the circuits in PFC needed for higher cognition. The layer III circuits in the dorsolateral PFC (dlPFC) that generate and sustain the mental representations needed for higher cognition have unusual neurotransmission and neuromodulation. They are wholly dependent on NMDAR neurotransmission, with little AMPAR contribution, and thus are especially vulnerable to kynurenic acid inflammatory signaling which blocks NMDAR. Layer III dlPFC spines also have unusual neuromodulation, with cAMP magnification of calcium signaling in spines, which opens nearby potassium channels to rapidly weaken connectivity and reduce neuronal firing. This process must be tightly regulated, e.g. by mGluR3 or α2A-AR on spines, to prevent loss of firing. However, the production of GCPII inflammatory signaling reduces mGluR3 actions and markedly diminishes dlPFC network firing. Both basic and clinical studies show that α2A-AR agonists such as guanfacine can restore dlPFC network firing and cognitive function, through direct actions in the dlPFC, but also by reducing the activity of stress-related circuits, e.g. in the locus coeruleus and amygdala, and by having anti-inflammatory actions in the immune system. This information is particularly timely, as guanfacine is currently the focus of large clinical trials for the treatment of delirium, and in open label studies for the treatment of cognitive deficits from long-COVID.

Retrospective: Patricia S. Goldman-Rakic, pioneer in neuroscience and co-founder of the journal, Cerebral Cortex.

Patricia Goldman-Rakic (1937-2003), the co-founder of this journal, was a pioneering neuroscientist who made transformational discoveries about the prefrontal cortex and the neurobiological basis of working memory. Her research served as the foundation for cognitive neuroscience, and paved the path for women in science. Her multidisciplinary approach created a new paradigm, where the scientific question, rather than a single method, was paramount to the investigation. The current review provides a brief summary of her extraordinary life and scientific contributions.

Localization of PDE4D, HCN1 channels, and mGluR3 in rhesus macaque entorhinal cortex may confer vulnerability in Alzheimer's disease.

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.

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

INTRODUCTION: Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. METHODS: We used multilabel 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. RESULTS: pT217-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 cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These 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.

Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders.

Glutamate carboxypeptidase-II (GCPII) expression in brain is increased by inflammation, e.g. by COVID19 infection, where it reduces NAAG stimulation of metabotropic glutamate receptor type 3 (mGluR3). GCPII-mGluR3 signaling is increasingly linked to higher cognition, as genetic alterations that weaken mGluR3 or increase GCPII signaling are associated with impaired cognition in humans. Recent evidence from macaque dorsolateral prefrontal cortex (dlPFC) shows that mGluR3 are expressed on dendritic spines, where they regulate cAMP-PKA opening of potassium (K+) channels to enhance neuronal firing during working memory. However, little is known about GCPII expression and function in the primate dlPFC, despite its relevance to inflammatory disorders. The present study used multiple label immunofluorescence and immunoelectron microscopy to localize GCPII in aging macaque dlPFC, and examined the effects of GCPII inhibition on dlPFC neuronal physiology and working memory function. GCPII was observed in astrocytes as expected, but also on neurons, including extensive expression in dendritic spines. Recordings in dlPFC from aged monkeys performing a working memory task found that iontophoresis of the GCPII inhibitors 2-MPPA or 2-PMPA markedly increased working memory-related neuronal firing and spatial tuning, enhancing neural representations. These beneficial effects were reversed by an mGluR2/3 antagonist, or by a cAMP-PKA activator, consistent with mGluR3 inhibition of cAMP-PKA-K+ channel signaling. Systemic administration of the brain penetrant inhibitor, 2-MPPA, significantly improved working memory performance without apparent side effects, with largest effects in the oldest monkeys. Taken together, these data endorse GCPII inhibition as a potential strategy for treating cognitive disorders associated with aging and/or neuroinflammation.

The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex.

Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer's disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without "bottom-up" sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP-PKA-calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP-PKA signaling. Excessive levels of cAMP-calcium signaling can have a number of detrimental effects: for example, opening nearby K+ channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium-cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium-cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3). Age-related loss of regulatory proteins which result in elevated calcium-cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the "genie" we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.

Alzheimer's-like pathology in aging rhesus macaques: Unique opportunity to study the etiology and treatment of Alzheimer's disease.

Although mouse models of Alzheimer's disease (AD) have provided tremendous breakthroughs, the etiology of later onset AD remains unknown. In particular, tau pathology in the association cortex is poorly replicated in mouse models. Aging rhesus monkeys naturally develop cognitive deficits, amyloid plaques, and the same qualitative pattern and sequence of tau pathology as humans, with tangles in the oldest animals. Thus, aging rhesus monkeys can play a key role in AD research. For example, aging monkeys can help reveal how synapses in the prefrontal association cortex are uniquely regulated compared to the primary sensory cortex in ways that render them vulnerable to calcium dysregulation and tau phosphorylation, resulting in the selective localization of tau pathology observed in AD. The ability to assay early tau phosphorylation states and perform high-quality immunoelectron microscopy in monkeys is a great advantage, as one can capture early-stage degeneration as it naturally occurs in situ. Our immunoelectron microscopy studies show that phosphorylated tau can induce an "endosomal traffic jam" that drives amyloid precursor protein cleavage to amyloid-ß in endosomes. As amyloid-ß increases tau phosphorylation, this creates a vicious cycle where varied precipitating factors all lead to a similar phenotype. These data may help explain why circuits with aggressive tau pathology (e.g., entorhinal cortex) may degenerate prior to producing significant amyloid pathology. Aging monkeys therefore can play an important role in identifying and testing potential therapeutics to protect the association cortex, including preventive therapies that are challenging to test in humans.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J.

INTRODUCTION: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. METHODS: We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. RESULTS: Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. CONCLUSION: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

Studies of aging nonhuman primates illuminate the etiology of early-stage Alzheimer's-like neuropathology: An evolutionary perspective.

Tau pathology in Alzheimer's disease (AD) preferentially afflicts the limbic and recently enlarged association cortices, causing a progression of mnemonic and cognitive deficits. Although genetic mouse models have helped reveal mechanisms underlying the rare, autosomal-dominant forms of AD, the etiology of the more common, sporadic form of AD remains unknown, and is challenging to study in mice due to their limited association cortex and lifespan. It is also difficult to study in human brains, as early-stage tau phosphorylation can degrade postmortem. In contrast, rhesus monkeys have extensive association cortices, are long-lived, and can undergo perfusion fixation to capture early-stage tau phosphorylation in situ. Most importantly, rhesus monkeys naturally develop amyloid plaques, neurofibrillary tangles comprised of hyperphosphorylated tau, synaptic loss, and cognitive deficits with advancing age, and thus can be used to identify the early molecular events that initiate and propel neuropathology in the aging association cortices. Studies to date suggest that the particular molecular signaling events needed for higher cognition-for example, high levels of calcium to maintain persistent neuronal firing- lead to tau phosphorylation and inflammation when dysregulated with advancing age. The expression of NMDAR-NR2B (GluN2B)-the subunit that fluxes high levels of calcium-increases over the cortical hierarchy and with the expansion of association cortex in primate evolution, consistent with patterns of tau pathology. In the rhesus monkey dorsolateral prefrontal cortex, spines contain NMDAR-NR2B and the molecular machinery to magnify internal calcium release near the synapse, as well as phosphodiesterases, mGluR3, and calbindin to regulate calcium signaling. Loss of regulation with inflammation and/or aging appears to be a key factor in initiating tau pathology. The vast expansion in the numbers of these synapses over primate evolution is consistent with the degree of tau pathology seen across species: marmoset < rhesus monkey < chimpanzee < human, culminating in the vast neurodegeneration seen in humans with AD.

Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease.

The etiology of the common, sporadic form of Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating that in human brains tau pathology appears about a decade before the formation of Aß plaques (Aßps), especially targeting glutamate projection neurons in the association cortex. Data from aging rhesus monkeys show abnormal tau phosphorylation within vulnerable neurons, associated with calcium dysregulation. Abnormally phosphorylated tau (pTau) on microtubules traps APP-containing endosomes, which can increase Aß production. As Aß oligomers increase abnormal phosphorylation of tau, this would drive vicious cycles leading to sAD pathology over a long lifespan, with genetic and environmental factors that may accelerate pathological events. This hypothesis could be testable in the aged monkey association cortex that naturally expresses characteristics capable of promoting and sustaining abnormal tau phosphorylation and Aß production.

Age-related calcium dysregulation linked with tau pathology and impaired cognition in non-human primates.

INTRODUCTION: The etiology of sporadic Alzheimer's disease (AD) requires non-genetically modified animal models. METHODS: The relationship of tau phosphorylation to calcium-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dysregulation was analyzed in aging rhesus macaque dorsolateral prefrontal cortex (dlPFC) and rat primary cortical neurons using biochemistry and immuno-electron microscopy. The influence of calcium leak from ryanodine receptors (RyRs) on neuronal firing and cognitive performance was examined in aged macaques. RESULTS: Aged monkeys naturally develop hyperphosphorylated tau, including AD biomarkers (AT8 (pS202/pT205) and pT217) and early tau pathology markers (pS214 and pS356) that correlated with evidence of increased calcium leak (pS2808-RyR2). Calcium also regulated early tau phosphorylation in vitro. Age-related reductions in the calcium-binding protein, calbindin, and in phosphodiesterase PDE4D were seen within dlPFC pyramidal cell dendrites. Blocking RyRs with S107 improved neuronal firing and cognitive performance in aged macaques. DISCUSSION: Dysregulated calcium signaling confers risk for tau pathology and provides a potential therapeutic target.

Noradrenergic α1-Adrenoceptor Actions in the Primate Dorsolateral Prefrontal Cortex.

Noradrenergic (NE) α1-adrenoceptors (α1-ARs) contribute to arousal mechanisms and play an important role in therapeutic medications such as those for the treatment of posttraumatic stress disorder (PTSD). However, little is known about how α1-AR stimulation influences neuronal firing in the dorsolateral prefrontal cortex (dlPFC), a newly evolved region that is dysfunctional in PTSD and other mental illnesses. The current study examined the effects of α1-AR manipulation on neuronal firing in dlPFC of rhesus monkeys performing a visuospatial working memory task, focusing on the "delay cells" that maintain spatially tuned information across the delay period. Iontophoresis of the α1-AR antagonist HEAT (2-{[ß-(4-hydroxyphenyl)ethyl]aminomethyl}-1-tetralone) had mixed effects, reducing firing in a majority of neurons but having nonsignificant excitatory effects or no effect in remaining delay cells. These data suggest that endogenous NE has excitatory effects in some delay cells under basal conditions. In contrast, the α1-AR agonists phenylephrine and cirazoline suppressed delay cell firing and this was blocked by coadministration of HEAT. These results indicate an inverted-U dose response for α1-AR actions, with mixed excitatory actions under basal conditions and suppressed firing with high levels of α1-AR stimulation such as with stress exposure. Immunoelectron microscopy revealed α1-AR expression presynaptically in axons and axon terminals and postsynaptically in spines, dendrites, and astrocytes. It is possible that α1-AR excitatory effects arise from presynaptic excitation of glutamate release, whereas postsynaptic actions suppress firing through calcium-protein kinase C opening of potassium channels on spines. The latter may predominate under stressful conditions, leading to loss of dlPFC regulation during uncontrollable stress.SIGNIFICANCE STATEMENT Noradrenergic stimulation of α1-adrenoceptors (α1-ARs) is implicated in posttraumatic stress disorder (PTSD) and other mental disorders that involve dysfunction of the prefrontal cortex, a brain region that provides top-down control. However, the location and contribution of α1-ARs to prefrontal cortical physiology in primates has received little attention. This study found that α1-ARs are located near prefrontal synapses and that α1-AR stimulation has mixed effects under basal conditions. However, high levels of α1-AR stimulation, as occur with stress, suppress neuronal firing. These findings help to explain why we lose top-down control under conditions of uncontrollable stress when there are high levels of noradrenergic release in brain and why blocking α1-AR, such as with prazosin, may be helpful in the treatment of PTSD.

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex.

BACKGROUND: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. METHODS: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. RESULTS: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. CONCLUSIONS: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

Guanfacine's mechanism of action in treating prefrontal cortical disorders: Successful translation across species.

The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K+) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC "offline" during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K+ channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine's beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine's benefits in a variety of mental disorders.

In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET.

INTRODUCTION: Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. METHODS: We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11 C]UCB-J PET and a cerebellar reference region for calculation of the distribution volume ratio. RESULTS: We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. CONCLUSION: We were able to measure widespread synaptic loss due to AD using [11 C]UCB-J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.