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Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.

The prefrontal cortex of the primate frontal lobes provides the capacity for judgment which can constantly adapt behavior in order to optimize its outcome. Adjudicating between long-term memory programs and prepotent responses, this capacity reviews all incoming information and provides an interpretation dependent on the events that have just occurred, the events that are predicted to happen, and the alternative response strategies that are available in the given situation. It has been theorized that this function requires two essential integrated components, a central executive which guides selective attention based on mechanisms of associative memory, as well as the second component, working memory buffers, in which information is held online, abstracted, and translated on a mental sketchpad of work in progress. In this review, we critically outline the evidence that the integration of these processes and, in particular, the induction and maintenance of persistent activity in prefrontal cortex and related networks, is dependent upon the interaction of dopamine D1 and glutamate NMDA receptor signaling at critical nodes within local circuits and distributed networks. We argue that this interaction is not only essential for representational memory, but also core to mechanisms of neuroadaptation and learning. Understanding its functional significance promises to reveal major new insights into prefrontal dysfunction in schizophrenia and, hence, to target a new generation of drugs designed to ameliorate the debilitating working memory deficits in this disorder.

Background: Nonhuman primates (NHPs) exhibit age‐related cognitive impairments, synaptic loss, and accumulation of tau and amyloid in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In a cohort of NHPs with longitudinal cognitive data, we perform SV2A ([11C]UCB‐J), amyloid ([11C]PIB), and tau ([18F]MK‐6240) PET. We aim to 1) investigate in vivo relationships and age‐related change in amyloid, tau, and synaptic density (SV2A) and 2) to relate these to cognition in NHPs. Method: Middle‐aged (n = 5, 10.4 ± 0.5 y.o.) and old (n = 17, 19.9 ± 2.7 y.o.) NHPs were dynamically PET scanned (FOCUS 220) following i.v. injection of each of [18F]MK‐6240 (173 ± 12 MBq), [ 11C]PIB (131 ± 52 MBq), and [11C]UCB‐J (105 ± 34 MBq). Structural MR scans were acquired for registering PET to template space. Outcome measures were SUVR40‐60 for [11C]PIB, SRTM2‐derived DVR for [11C]UCB‐J, and SUVR90‐110 for [18F]MK‐6240. Cerebellum was used as reference ([11C]PIB, [11C]UCB‐J), and cerebellar gray matter for [18F]MK‐6240. A subset of the old NHPs (n = 15) were tested with the spatial‐delayed response task to assess working memory performance. Outcome measures: number‐of‐wells, time‐delay, and combined score (number‐of‐wells × time‐delay); higher score indicates better memory performance. Result: No regional mean differences were observed in amyloid or SV2A between middle‐aged and old NHPs, though old NHPs exhibited higher variance for all tracers; mean tau was elevated in dlPFC (p = 0.0031) and hippocampus (HC, p = 0.011) in old NHP compared with middle‐aged (Figure 1). In ERC, a positive relationship was found between tau and amyloid), and in HC, a negative correlation was found between tau and SV2A (Figure 2A). Synaptic density displayed a positive relationship with combined score both in dlPFC (p = 0.0055, R2 = 0.46) and HC (p = 0.029, R2 = 0.32) (Figure 2B). Tau had a negative relationship with number‐of‐wells in dlPFC (p = 0.05, R2 = 0.40), and combined score in HC (p = 0.015, R2 = 0.40). Conclusion: NHPs exhibit age‐related changes in canonical AD biomarkers as seen by PET. PET markers of SV2A, tau, and amyloid in known early‐pathology regions (dlPFC, HC) correlate appropriately with working memory performance. These studies demonstrate the potential of NHPs as a highly useful model for human AD. [ABSTRACT FROM AUTHOR]

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the a7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamineinduced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia. [ABSTRACT FROM AUTHOR]

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3½ years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.38±7.65 μm in AMPH-sensitized compared to 162.98±7.26 μm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia.Neuropsychopharmacology (2007) 32, 919–931. doi:10.1038/sj.npp.1301179; published online 16 August 2006 [ABSTRACT FROM AUTHOR]

Background and rationale. Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D1 receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D1 stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia. Objectives. This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D1 signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function. Results and conclusions. Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D1 receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D1 receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia. [ABSTRACT FROM AUTHOR]

A natural consequence of aging is a loss of dopamine function and associated deficits in working memory in both human and nonhuman primates. Specifically, deficiency of D1 receptor signaling has been implicated in age-related cognitive decline. Here, we report that an intermittent, sensitizing regimen of the D1 dopamine agonist ABT-431 dramatically enhances working memory performance in aged rhesus monkeys, while either producing impairment or having little effect on performance in young adult monkeys. Importantly, cognitive enhancement in the aged monkeys was still evident for > 1 year after cessation of D1 treatment. Because intermittent exposure to low doses of amphetamine and other stimulants has been shown to enhance responsiveness to subsequent stimulant exposure, our findings suggest that sensitization of D1 signaling may provide a novel neurobiological mechanism for improving a core cognitive process in conditions in which dopamine function has deteriorated, such as in normal aging and Parkinson's disease. [ABSTRACT FROM AUTHOR]