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Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo . Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry. Adult neurogenesis in the mammalian brain is implicated in the storage and processing of memories. Vivar et al. label afferents to new dentate gyrus granule cells and find that they receive direct input from the perirhinal and lateral entorhinal cortex and that these inputs enable spatial pattern separation.

Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the α7 nicotinic acetylcholine receptor (α7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30–300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor ( S )-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3–3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 μl) or ESBA (10 mM, 10 μl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 μM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the α 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (−71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro . These functional changes were accompanied by reduced extracellular KYNA (−66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo . Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.

The accumulation of excess glutamate in the extracellular space as a consequence of CNS trauma, neurodegenerative diseases, infection, or deregulation of glutamate clearance results in neuronal damage by excessive excitatory neurotransmission. Glutamate excitotoxicity is thought to be one of several mechanisms by which HIV exerts neurotoxicity that culminates in HIV-associated neurocognitive disorders (HAND). Excess glutamate is released upon HIV infection of macrophage/microglial cells and has been associated with neurotoxicity mediated by gp120, transactivator of transcription (Tat) and other HIV proteins. Several strategies have been used over the years to try to prevent glutamate excitotoxicity. Since the main toxic effects of excess glutamate are thought to be due to excitotoxicity from over activation of glutamate receptors, antagonists of these receptors have been popular therapeutic targets. Early work to ameliorate the effects of excess extracellular glutamate focused on NMDA receptor antagonism, but unfortunately, potent blockade of this receptor has been fraught with side effects. One alternative to direct receptor blockade has been the inhibition of enzymes responsible for the production of glutamate such as glutaminase and glutamate carboxypeptidase II. Another approach has been to regulate the transporters responsible for modulation of extracellular glutamate such as excitatory amino acid transporters and the glutamate-cystine antiporter. There is preliminary experimental evidence that these approaches have potential therapeutic utility for the treatment of HAND. These efforts however, are at an early stage where the next steps are dependent on the identification of drug-like inhibitors as well as the development of predictive neuroAIDS animal models.

Pyridoxine is used as a supplement for treating conditions such as vitamin deficiency as well as neurological disorders such as depression, epilepsy and autism. A significant neurologic complication of pyridoxine therapy is peripheral neuropathy thought to be a result of long-term and high dose usage. Although pyridoxine-induced neuropathy is transient and can remit after its withdrawal, the process of complete recovery can be slow. Glutamate carboxypeptidase II (GCP II) inhibition has been shown to improve symptoms of both chemotherapy- and diabetic-induced neuropathy. This study evaluated if GCP II inhibition could behaviorally and physiologically improve pyridoxine-induced neuropathy. In the current study, high doses of pyridoxine (400 mg/kg, twice a day for seven days) were used to induce neuropathy in rats. An orally bioavailable GCP II inhibitor, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), was administered daily at a dose of 30 mg/kg starting from the onset of pyridoxine injections. Body weight, motor coordination, heat sensitivity, electromyographical (EMG) parameters and nerve morphological features were monitored. The results show beneficial effects of GCP II inhibition including normalization of hot plate reaction time, foot fault improvements and increased open field distance travelled. H wave frequency, amplitude and latency as well as sensory nerve conduction velocity (SNCV) were also significantly improved by 2-MPPA. Lastly, GCP II inhibition resulted in morphological protection in the spinal cord and sensory fibers in the lumbar region dorsal root ganglia (DRG). In conclusion, inhibition of GCP II may be beneficial against the peripheral sensory neuropathy caused by pyridoxine.

Recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. Infection of mice with the prototypic alphavirus, Sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. Infectious virus is cleared from the brain within a week after infection, but viral RNA is cleared slowly and persists for the life of the animal. However, no studies have examined the effect of infection on neurocognitive function over time. In the present study, we examined neurocognitive function at different phases of infection in 5-week-old C57BL/6 mice intranasally inoculated with Sindbis virus. At the peak of active virus infection, mice demonstrated hyperactivity, decreased anxiety, and marked hippocampal-dependent memory deficits, the latter of which persisted beyond clearance of infectious virus and resolution of clinical signs of disease. Previous studies indicate that neuronal damage during alphavirus encephalomyelitis is primarily due to inflammatory cell infiltration and glutamate excitotoxicity rather than directly by virus infection. Therefore, mice were treated with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist that can suppress both the immune response and excitotoxicity. Treatment with DON decreased inflammatory cell infiltration and cell death in the hippocampus and partially prevented development of clinical signs and neurocognitive impairment despite the presence of infectious virus and high viral RNA levels. This study presents the first report of neurocognitive sequelae in mice with alphavirus encephalomyelitis and provides a model system for further elucidation of the pathogenesis of virus infection and assessment of potential therapies.

Kynurenic acid (KYNA) is an endogenous brain metabolite produced by the kynurenine pathway of tryptophan degradation. It acts as an antagonist of the N-methyl-D-aspartate (NMDA) and alpha 7 nicotinic acetylcholine (a7nACh) receptors, which are involved in glutamatergic and cholinergic neurotransmission and are critical to an efficiently functioning learning and memory system. The hippocampus, a brain area intricately involved in learning and memory, is innervated by both glutamatergic and cholinergic neurons and contains abundant NMDA and a7nACh receptors. This thesis was designed to study if modulation of glutamatergic and cholinergic function by KYNA plays a role in hippocampal-dependent learning and memory. In FVB/N mice, genomic elimination of kynurenine aminotransferase II (KAT II), the main enzyme responsible for KYNA production in the brain, caused a reduction in hippocampal KYNA levels on postnatal day (PND) 21. This was accompanied by increased extracellular hippocampal glutamate levels and improved performance in some well-established learning and memory paradigms. Mutant PND 21 129SvEv mice also displayed reduced KYNA levels, however without similar changes in glutamate levels or performance on the passive avoidance task. At PND 90, when brain KYNA levels in mutant FVB/N mice returned to wild-type levels, cognitive performance of knock-out mice in some, but not all, tasks did not differ from controls. Moreover, acute normalization of KYNA levels in PND 21 KAT II knock-out FVB/N mice did not attenuate the increase in glutamate levels or the improvement in performance on the passive avoidance task. In the rat hippocampus, a bi-directional control of glutamate by KYNA was revealed, with increases in KYNA levels reducing and decreases in KYNA levels raising extracellular glutamate levels. These drug-induced acute changes were subsequently used to evaluate the role of fluctuating KYNA levels in hippocampal-dependent learning and memory tasks. Decreased KYNA levels caused cognitive improvements in Morris water maze performance but not in passive avoidance or object recognition learning. Acutely elevated KYNA levels did not influence performance in the passive avoidance task. Overall, these results indicate that KYNA plays a role in aspects of hippocampal-dependent learning and memory, and this effect appears to be mediated by the glutamatergic system.

Background Online dietary assessment tools can reduce administrative costs and facilitate repeated dietary assessment during follow-up in large-scale studies. However, information on bias due to measurement error of such tools is limited. We developed an online 24-h recall (myfood24) and compared its performance with a traditional interviewer-administered multiple-pass 24-h recall, assessing both against biomarkers. Methods Metabolically stable adults were recruited and completed the new online dietary recall, an interviewer-based multiple pass recall and a suite of reference measures. Longer-term dietary intake was estimated from up to 3 × 24-h recalls taken 2 weeks apart. Estimated intakes of protein, potassium and sodium were compared with urinary biomarker concentrations. Estimated total sugar intake was compared with a predictive biomarker and estimated energy intake compared with energy expenditure measured by accelerometry and calorimetry. Nutrient intakes were also compared to those derived from an interviewer-administered multiple-pass 24-h recall. Results Biomarker samples were received from 212 participants on at least one occasion. Both self-reported dietary assessment tools led to attenuation compared to biomarkers. The online tools resulted in attenuation factors of around 0.2–0.3 and partial correlation coefficients, reflecting ranking intakes, of approximately 0.3–0.4. This was broadly similar to the more administratively burdensome interviewer-based tool. Other nutrient estimates derived from myfood24 were around 10–20% lower than those from the interviewer-based tool, with wide limits of agreement. Intraclass correlation coefficients were approximately 0.4–0.5, indicating consistent moderate agreement. Conclusions Our findings show that, whilst results from both measures of self-reported diet are attenuated compared to biomarker measures, the myfood24 online 24-h recall is comparable to the more time-consuming and costly interviewer-based 24-h recall across a range of measures.