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Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl‐prolyl cis/trans isomerase, NIMA‐Interacting 1 (PIN1) is a peptidyl‐prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over‐expression is linked to cancer. Death‐associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high‐level signaling molecules, such as nuclear factor erythroid 2‐related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism. [ABSTRACT FROM AUTHOR]

Cholecystokinin (CCK) has been confirmed to be essential in NMDA‐dependent long‐term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high‐frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity‐induced LTP by triggering pre‐synaptic CCK release. A functional pre‐synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK‐specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity‐induced LTP at the hippocampal synapse is CCK‐dependent, and CCK secretion from the axonal terminal is modulated by pre‐synaptic NMDA receptors. [ABSTRACT FROM AUTHOR]

Isotopic assays of brain glucose utilization rates have been used for more than four decades to establish relationships between energetics, functional activity, and neurotransmitter cycling. Limitations of these methods include the relatively long time (1–60 min) for the determination of labeled metabolite levels and the lack of cellular resolution. Identification and quantification of fuels for neurons and astrocytes that support activation and higher brain functions are a major, unresolved issues. Glycolysis is preferentially up-regulated during activation even though oxygen level and supply are adequate, causing lactate concentrations to quickly rise during alerting, sensory processing, cognitive tasks, and memory consolidation. However, the fate of lactate (rapid release from brain or cell–cell shuttling coupled with local oxidation) is long disputed. Genetically encoded biosensors can determine intracellular metabolite concentrations and report real-time lactate level responses to sensory, behavioral, and biochemical challenges at the cellular level. Kinetics and time courses of cellular lactate concentration changes are informative, but accurate biosensor calibration is required for quantitative comparisons of lactate levels in astrocytes and neurons. An in vivo calibration procedure for the Laconic lactate biosensor involves intracellular lactate depletion by intravenous pyruvate-mediated trans-acceleration of lactate efflux followed by sensor saturation by intravenous infusion of high doses of lactate plus ammonium chloride. In the present paper, the validity of this procedure is questioned because rapid lactate–pyruvate interconversion in blood, preferential neuronal oxidation of both monocarboxylates, on-going glycolytic metabolism, and cellular volumes were not taken into account. Calibration pitfalls for the Laconic lactate biosensor also apply to other metabolite biosensors that are standardized in vivo by infusion of substrates that can be metabolized in peripheral tissues. We discuss how technical shortcomings negate the conclusion that Laconic sensor calibrations support the existence of an in vivo astrocyte–neuron lactate concentration gradient linked to lactate shuttling from astrocytes to neurons to fuel neuronal activity. [ABSTRACT FROM AUTHOR]

While brain glucose metabolism is known to contribute the carbons to support brain saturated and monounsaturated fatty biosynthesis de novo in the developing brains of young rodents, such a contribution to fatty acid biosynthesis in the adult brain is poorly understood. Recent work from the Bazinet laboratory illuminates the role of brain glucose metabolism in providing a carbon source from which palmitic acid is synthesized. In "The Majority of Brain Palmitic Acid is Maintained by Lipogenesis from Dietary Sugars and is Augmented in Offspring fed low Palmitic Acid Levels from Birth", the Bazinet lab demonstrates the importance of glucose as a key contributing source of carbon for brain palmitic synthesis and that a low palmitate diet exacerbates its utilization for brain palmitate synthesis de novo. Further, this impact is found in male mice rather than female mice, which adds an additional layer of importance. Mammals are known to conserve carbon and the brain has the ability to convert a variety of carbon sources to needed molecules, depending on the physiological needs of the brain. Overall, this paper contributes an important missing piece of the puzzle regarding carbon recycling in the brain and is a key piece of evidence that indeed the adult mammalian brain can convert glucose to carbons for use in saturated fatty acid synthesis. [ABSTRACT FROM AUTHOR]

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3‐hydroxykynurenine (3‐HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G‐protein‐coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+‐dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain‐specific properties in balance with its formation and peripheral inputs. [ABSTRACT FROM AUTHOR]

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs‐based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs‐based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS‐specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double‐blind, randomized, placebo‐controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient‐derived iPSCs‐motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA‐seq data showed that ROPI treatment suppressed the sterol regulatory element‐binding protein 2‐dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper. [ABSTRACT FROM AUTHOR]

Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that mGlu3R activation in astrocytes protects hippocampal neurons from Aβ neurotoxicity through stimulation of both neurotrophin release and Aβ uptake. Alternative‐spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. To date, neither its role in neurodegenerative disorders nor its endogenous expression in CNS cells has been addressed. The present paper describes for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer's disease (AD) in the preclinical murine model PDAPP‐J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP‐J20 mice. On the contrary, mGlu3Δ4 levels were drastically increased with aging in nontransgenic mice, but prematurely over‐expressed in 5‐month‐old PDAPP‐J20‐derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3Δ4 co‐precipitated with mGlu3R mainly in 5‐month‐old PDAPP‐J20 mice. We further showed by western blot that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aβ, thereby discouraging a causal effect of Aβ on mGlu3Δ4 induction. However, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R‐dependent Aβ glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron–glia co‐cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R‐mediated glial neuroprotective pathways, which may lie behind AD onset. [ABSTRACT FROM AUTHOR]

The most obvious difference in science publishing between 'then' and 'now' is the dramatic change in the communication of data and in their interpretation. The democratization of science via the Internet has brought not only benefits but also challenges to publishing including fraudulent behavior and plagiarism, data and statistics reporting standards, authorship confirmation and other issues which affect authors, readers, and publishers in different ways. The wide accessibility of data on a global scale permits acquisition and meta-analysis to mine for novel synergies, and has created a highly commercialized environment. As we illustrate here, identifying unacceptable practices leads to changes in the standards for data reporting. [ABSTRACT FROM AUTHOR]

Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre‐registration of a review protocol, we systematically searched the PubMed, EMBASE, and Cochrane databases for literature covering themes of 'lactate', 'the brain', and 'microcirculation'. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty‐eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose‐dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD+/NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose‐dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. Open Science Badges: This article has received a badge for *Pre‐registration* because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer%5flactate%5fprotocol.aspx. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. This systematic review evaluated the role of lactate in the cerebral microcirculation across in vitro, in vivo, and clinical studies. We identified that when administered exogenously, at 5 mmol/kg or higher, lactate is an initiator of cerebral hyperemia and acts as an augmenter of functional hyperemia at lower doses. These findings shine light on novel aspects of lactate biochemistry in the brain. This manuscript was awarded with the Pre‐registration Badge. The pre‐registration protocol can be accessed at http://www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer%5flactate%5fprotocol.aspx. For more information see: https://cos.io/our-services/open-science-badges/ [ABSTRACT FROM AUTHOR]

Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta‐regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (p ≥ 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post‐surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta‐regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve. Microdialysis has long been used to measure neurotransmitters, with overwhelming variations in experimental designs. A systematic literature review is the optimal method to acquire a complete overview. We systematically reviewed the literature for baseline concentrations of adenosine in microdialysates. We then performed a meta‐regression analysis to study the effects of variations in experimental design. This study shows that meta‐regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. Therefore, the standard of experimental detail reporting needs to improve. Picture by Julia M.L. Menon, syringe and vial adapted from Servier medical art. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) affects a significant proportion of the population over the age of 60 years, and its prevalence is increasing. While symptomatic treatment is available for motor symptoms of PD, non‐motor complications such as dementia result in diminished life quality for patients and are far more difficult to treat. In this study, we analyzed PD‐associated alterations in the hippocampus of PD patients, since this brain region is strongly affected by PD dementia. We focused on synapses, analyzing the proteome of post‐mortal hippocampal tissue from 16 PD cases and 14 control subjects by mass spectrometry. Whole tissue lysates and synaptosomal fractions were analyzed in parallel. Differential analysis combined with bioinformatic network analyses identified neuronal pentraxin 1 (NPTX1) to be significantly dysregulated in PD and interacting with proteins of the synaptic compartment. Modulation of NPTX1 protein levels in primary hippocampal neuron cultures validated its role in synapse morphology. Our analysis suggests that NPTX1 contributes to synaptic pathology in late‐stage PD and represents a putative target for novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

The neurotensin system spans across the central nervous system, to the enteric nervous system (gut), and the periphery to govern behaviors and physiological responses that tune energy balance to maintain homeostasis. Neurotensin transmission is not only modulated by metabolic signals, neurotensin transmission itself can also impact metabolic state by exerting control over consumption, physical activity, and satiety signals. Many responses to sensory experiences and sleep processes are dictated by neurotensinergic activity via mechanisms that allow the organism to balance energy seeking and utilization to thrive in its environment. Given the broad reach neurotensin signaling has across the homeostatic landscape, understanding this system as a whole and examining new ways to target this system for therapeutic efficacy across many different conditions is necessary. [ABSTRACT FROM AUTHOR]

This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM‐XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems. [ABSTRACT FROM AUTHOR]

Microglia play a vital role in maintaining brain homeostasis. Their continuous sensing of surrounding micro‐environments is crucial for their activity. Cross talk between specific neurons and microglia might occur through specific neurotransmitter receptors on microglia. Impairment with this interaction might result in pathological activity of microglia against potential insults. The reason for this activity in many neurodegenerative diseases such as Alzheimer's disease (AD) is not known. However, several papers report of the effects of different neurotransmitter agonists on microglial cells function that relate to their activity in AD. This review aims to summarize those works and to raise potential fundamental questions for future research. [ABSTRACT FROM AUTHOR]

Extracellular plaque deposits of ß-amyloid peptide (Aß) are one of the main pathological features of Alzheimer's disease (AD). The aggregation of Aß42 species, especially Aß42 oligomers, is still an active research field in AD pathogenesis. Secretory clusterin protein (sCLU), an extracellular chaperone, plays an important role in AD pathogenesis. Although sCLU interacts directly with Aß42 in vitro and in vivo, the mechanism is not clear. In this paper, His-tagged sCLU (sCLU-His) was cloned, expressed and purified, and we applied florescence resonance energy transfer-fluorescence correlation spectroscopy (FRET-FCS) to investigate the direct interaction of sCLU-His and Aß42 at the single-molecule fluorescence level in vitro. Here, we chose four different fluorescently labeled Aß42 oligomers to form two different groups of aggregation models, easy or difficult to aggregate. The results showed that sCLU-His could form complexes with both aggregation models, and sCLU-His inhibited the aggregation of Aß42/RB ~ Aß42/Atto647 (easy to aggregate model). The complexes were produced as the Aß42/Label adhered to the sCLU-His, which is similar to a "strawberry model," as strawberry seeds are dotted on the outer surface of strawberries. This work provided additional insight into the interaction mechanism of sCLU and Aß42. [ABSTRACT FROM AUTHOR]

Extracellular plaque deposits of β‐amyloid peptide (Aβ) are one of the main pathological features of Alzheimer's disease (AD). The aggregation of Aβ42 species, especially Aβ42 oligomers, is still an active research field in AD pathogenesis. Secretory clusterin protein (sCLU), an extracellular chaperone, plays an important role in AD pathogenesis. Although sCLU interacts directly with Aβ42 in vitro and in vivo, the mechanism is not clear. In this paper, His‐tagged sCLU (sCLU‐His) was cloned, expressed and purified, and we applied florescence resonance energy transfer‐fluorescence correlation spectroscopy (FRET‐FCS) to investigate the direct interaction of sCLU‐His and Aβ42 at the single‐molecule fluorescence level in vitro. Here, we chose four different fluorescently labeled Aβ42 oligomers to form two different groups of aggregation models, easy or difficult to aggregate. The results showed that sCLU‐His could form complexes with both aggregation models, and sCLU‐His inhibited the aggregation of Aβ42/RB ~ Aβ42/Atto647 (easy to aggregate model). The complexes were produced as the Aβ42/Label adhered to the sCLU‐His, which is similar to a "strawberry model," as strawberry seeds are dotted on the outer surface of strawberries. This work provided additional insight into the interaction mechanism of sCLU and Aβ42. [ABSTRACT FROM AUTHOR]

Many journals, including the Journal of Neurochemistry, enable authors to list peer reviewers as 'preferred' or 'opposed' suggestions to the editor. At the Journal of Neurochemistry, the handling editor (HE) may follow recommendations or select non-author-suggested reviewers (non-ASRs). We investigated whether selection of authorsuggested reviewers (ASRs) influenced decisions on a paper, and whether differences might be related to a reviewer's, editor's or manuscript's geographical location. In this retrospective analysis, we compared original research articles submitted to the Journal of Neurochemistry from 2013 through 2016 that were either reviewed exclusively by non-ASRs, by at least one ASR, by at least one reviewer marked by the author as 'opposed' or none. Manuscript outcome, reviewer rating of manuscript quality, rating of the reviewers' performance by the editor (R-score), time to review, and the country of the editor, reviewers and manuscript author were analyzed using non-parametric rank-based comparisons, chisquare (x2) analysis, multivariate linear regression, one-way analysis of variance, and inter-rater reliability determination. Original research articles that had been reviewed by at least one ASR stood a higher chance of being accepted (525/1006 = 52%) than papers that had been reviewed by non-ASRs only (579/1800 = 32%). An article was 2.4 times more likely to be accepted than rejected by an ASR compared to a non-ASR (Pearson's x2(1) = 181.3, p < 0.05). At decision, the editor did not simply follow the reviewers' recommendation but had a balancing role: Rates of recommendation from reviewers for rejection were 11.2% (139/1241) with ASRs versus 29.0% (1379/4755) with non-ASRs (this is a ratio of 0.39 where 1 means no difference between rejection rates for both groups), whereas the proportion of final decisions to reject was 24.7% (248/1006) versus 45.7% (822/1800) (a ratio of 0.54, considerably closer to 1). Recommendations by non-ASRs were more favorable for manuscripts from USA/Canada and Europe than for Asia/Pacific or Other countries. ASRs judged North American manuscripts most favorably, and judged papers generally more positively (mean: 2.54 on a 1-5 scale) than did non-ASRs (mean: 3.16) reviewers, whereas time for review (13.28 vs. 13.20 days) did not differ significantly between these groups. We also found that editors preferably assigned reviewers from their own geographical region, but there was no tendency for reviewers to judge papers from their own region more favorably. Our findings strongly confirm a bias toward lower rejection rates when ASRs assess a paper, which led to the decision to abandon the option to recommend reviewers at the Journal of Neurochemistry. [ABSTRACT FROM AUTHOR]

Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug‐stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug that is misused. Clinical and preclinical studies have suggested that repeated MDMA exposure produces neuroadaptive responses in both 5HT and DA neurotransmission that might explain the development and maintenance of MDMA self‐administration in some laboratory animals and the development of a substance use disorder in some humans. In this paper, we describe the research that has demonstrated an inhibitory effect of 5HT on the acquisition of MDMA self‐administration and the critical role of DA in the maintenance of MDMA self‐administration in laboratory animals. We then describe the circuitry and 5HT receptors that are positioned to modulate DA activity and review the limited research on the effects of MDMA exposure on these receptor mechanisms. [ABSTRACT FROM AUTHOR]