A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.

Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.

Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders.

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system (CNS) and result in their damage and death. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes. The treatment of neurodegenerative and neurodevelopmental conditions, together affecting ∼120 million people worldwide, is challenged by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS. The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions. This pathway is more efficient for nanoparticles than for solutions, hence, the research on intranasal nano-drug delivery systems has grown exponentially over the last decade. Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility. This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions, the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them. Then, a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

Emotional and sensory dysregulation as a possible missing link in attention deficit hyperactivity disorder: A review.

Attention Deficit Hyperactivity Disorder (ADHD) is a common developmental disorder affecting 5-7% of adults and children. We surveyed the literature to examine ADHD through three pillars: developmental characteristics, symptomatology, and treatment strategies. Firstly, in terms of developmental characterstics, early life stress may increase the risk of developing ADHD symptoms according to animal models' research. Secondly, the current core symptoms of ADHD are comprised of inattention, hyperactivity, and impulsivity. However, the up-to-date literature indicates individuals with ADHD experience emotional and sensory dysregulation as well, which early-life stress may also increase the risk of. Finally, we discuss the therapeutic benefits of methylphenidate on both the current core ADHD symptoms and the sensory and emotional dysregulation found in those with ADHD. In summation, we surveyed the recent literature to analyze (i) the potential role of early-life stress in ADHD development, (ii) the involvement of emotional and sensory dysregulation in ADHD symptomatology and finally, (iii) the therapeutic intervention with methylphenidate, aiming to reduce the potential effect of early life stress in ADHD, and mainly emotional and sensory dysregulation. The apparent but currently less recognized additional symptoms of emotional and sensory dysregulation in ADHD call for further investigation of these possible causes and thus increasing treatments efficacy in individuals with ADHD.

Attention deficits as a key player in the symptomatology of posttraumatic stress disorder: A review.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder characterized by symptoms such as re-experiencing of the psychotrauma and hyperarousal. Although current literature mainly discusses the emotionally related aspects of these symptoms, studies also highlight the relation between re-experiencing, hyperarousability, and attention deficits, which are associated with poorer daily function and reduced quality of life. This review provides a comprehensive analysis of the existing research on attention deficits among adults with PTSD. A systematic search through five databases resulted in the inclusion of 48 peer-reviewed, English-language articles, describing 49 distinct studies. Using a total of 47 different attentional assessment tools, the majority of studies investigated sustained (n = 40), divided (n = 16), or selective (n = 14) attention. A total of 30 studies (61.2%) found significant correlations between PTSD symptoms and attention deficits, and 10 studies (20.4%) found that higher levels of attention deficits were predictive of worse PTSD symptoms. Moreover, neuroimaging results of six (f)MRI and three EEG studies identified various potential neurobiological pathways involved, including (pre)frontal attention networks. Together, the body of research shows that attention deficits in individuals with PTSD are common and occur in surroundings with emotionally neutral stimuli. Nonetheless, current treatment strategies do not target these attentional difficulties. We propose a novel perspective to PTSD diagnosis and treatment strategies based on attention deficits and their relation with top-down regulation of re-experiencing and subsequent other PTSD symptoms.

Exposure to static magnetic field facilitates selective attention and neuroplasticity in rats.

Static magnetic fields (SMF) have neuroprotective and behavioral effects in rats, however, little is known about the effects of SMF on cognition, motor function and the underlying neurochemical mechanisms. In this study, we focused on the effects of short-term (5-10d) and long-term (13-38d) SMF exposure on selective attention and motor coordination of rats, as well as associated alterations in expression level of neuroplasticity-related structural proteins and cryptochrome (CRY1) protein in the cortex, striatum and ventral midbrain. The results showed that 6d SMF exposure significantly enhanced selective attention without affecting locomotor activity in open field. All SMF exposures non-significantly enhanced motor coordination (Rotarod test). Neurochemical analysis demonstrated that 5d SMF exposure increased the expression of cortical and striatal CRY1 and synapsin-1 (SYN1), striatal total synapsins (SYN), and synaptophysin (SYP), growth associated protein-43 (GAP43) and post-synaptic density protein-95 (PSD95) in the ventral midbrain. Exposure to SMF for 14d increased PSD95 level in the ventral midbrain while longer SMF exposure elevated the levels of PSD95 in the cortex, SYN and SYN1 in all the examined brain areas. The increased expression of cortical and striatal CRY1 and SYN1 correlated with the short-lasting effect of SMF on improving selective attention. Collectively, SMF's effect on selective attention attenuated following longer exposure to SMF whereas its effects on neuroplasticity-related structural biomarkers were time- and brain area-dependent, with some protein levels increasing with longer time exposure. These findings suggest a potential use of SMF for treatment of neurological diseases in which selective attention or neuroplasticity is impaired.

Differential Impact of Work Overload on Physicians' Attention: A Comparison Between Residential Fields.

OBJECTIVES: Medical errors cause tens of thousands of deaths annually and have a major impact on quality of care and management; however, it receives scant research and public awareness. This study aimed to examine the relation between workload-induced lack of sleep and attention failure, as indications for medical errors risk, among young residents. METHODS: We performed an evaluation of young physicians by the Test of Variables of Attention, before and after a 24-hour shift. RESULTS: Workload was manifested by 13% overall attention impairment at baseline, which increased to 34% with deficiencies below the normal range after the shift. Attention measures differed between physicians of each residential field at baseline, but to greater extent after the shift. CONCLUSIONS: Traditional working schedule is strongly associated with attention failure. Based on the literature linking attention failures to medical errors, we suggest a regulatory change regarding residents' shift duration to decrease preventable errors.

Dog training alleviates PTSD symptomatology by emotional and attentional regulation.

Background: Post-Traumatic Stress Disorder (PTSD) symptoms include re-experiencing, avoidance, hyperarousal, and cognitive deficits, reflecting both emotional and cognitive dysregulation. In recent years, non-pharmacological approaches and specifically animal-assisted therapy have been shown to be beneficial for a variety of disorders such as Attention-Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, and PTSD. However, little is mentioned in the literature about the reciprocal effects of the animal-human interaction. Objective: To evaluate the effects of a one-year dog training programme on PTSD symptomatology in youngsters with PTSD and on dogs' behaviour. Methods: Fifty-three adolescents, previously exposed to interpersonal trauma, were clinically diagnosed with PTSD and assigned to a dog-training programme group (n = 30) and a control group (n = 23) that engaged in other training programmes (e.g. cooking, hairstyling, etc.). Both groups were evaluated at baseline and following 12-months by The Clinician-Administered PTSD Scale for DSM-5 in Children and Adolescents (CAPS-CA-5) and Beck-Depression Inventory (BDI). Additionally, we physiologically measured both emotional and attention dysregulation. Results: Post-12-months training, a significant alleviation of PTSD symptomatology accompanied by lower depression severity was observed in the dog-training group, compared with a insignificant recovery in the control group. Furthermore, improved emotional and attentional regulation was observed in the dog-training group. Measuring the dogs' behaviour revealed increased anxiety and decreased selective attention performance, which was inversely correlated with the beneficial effects observed in the dog-training programme group. Conclusions: Our findings emphasize the role of emotional and attentional regulations on the dog-handler interface, as evidence-based support for the beneficial effects of the dog-training programme, as either a non-pharmacological intervention or as complementary to anti-depressants treatment of PTSD. Though pharmacological treatments increase the patients' well-being by treating certain PTSD symptoms, our suggested dog-training programme seems to influence the PTSD diagnostic status, thus may be implemented in civilians and veterans with PTSD.

Antecedentes: Los síntomas de trastorno de estrés postraumático (TEPT) incluyen re-experimentación, evitación, hiperalerta y déficits cognitivos, reflejando desregulación tanto emocional como cognitiva. En los últimos años, se demostró que los enfoques no farmacológicos y específicamente la terapia asistida por animales son beneficiosos para una variedad de trastornos como el Trastorno por Déficit Atencional e Hiperactividad, el Trastorno del Espectro Autista y el TEPT. Sin embargo, poco se menciona en la literatura acerca de los efectos recíprocos de la interacción animal-humano.Objetivo: Evaluar los efectos de un programa de adiestramiento canino de un año en la sintomatología de TEPT en los jóvenes con TEPT y en el comportamiento de los perros.Métodos: Cincuenta y tres adolescentes, previamente expuestos a trauma interpersonal, fueron diagnosticados clínicamente con TEPT y asignados a un grupo de programa de adiestramiento canino (n = 30) y a un grupo control (n = 23) que participaron en otros programas de adiestramiento (ej., cocinar, peluquería, etc). Ambos grupos fueron evaluados al inicio y después de 12 meses mediante la Escala de TEPT administrada por el Clínico del DSM-5 en niños y adolescentes (CAPS-CA-5 por sus siglas en inglés) y el Inventario de Depresión de Beck (BDI). Adicionalmente, medimos fisiológicamente la desregulación emocional y de la atención.Resultados: Después del entrenamiento de 12 meses, se observó un alivio significativo de la sintomatología de TEPT junto con una disminución de la severidad de la depresión en el grupo de adiestramiento canino, comparado con una recuperación insignificante en el grupo control. Además, se observó una mejoría en la regulación emocional y de la atención en el grupo de adiestramiento canino. La medición del comportamiento de los perros reveló un aumento de la ansiedad y disminución del rendimiento de la atención selectiva, que se correlacionó inversamente con los efectos beneficiosos observados en el grupo del programa de adiestramiento canino.Conclusiones: Nuestros hallazgos enfatizan el rol de la regulación emocional y de atención en la interfaz del entrenador de perros, como soporte basado en la evidencia para los efectos beneficiosos del programa de adiestramiento canino, tanto como tratamiento no farmacológico como complementario al tratamiento antidepresivo del TEPT. Aunque los tratamientos farmacológicos fomentan el bienestar de los pacientes al tratar ciertos síntomas del TEPT, nuestro programa de adiestramiento canino sugerido parece influir en el estado diagnóstico de TEPT, por lo que puede implementarse en civiles y veteranos con TEPT.

Attention Dysregulation in Breast Cancer Patients Following a Complementary Alternative Treatment Routine: A Double-Blind Randomized Trial.

INTRODUCTION: Breast cancer patients and survivors frequently report fatigue, emotional, and cognitive disturbances, which reduce performance at all levels of occupation and make life quality issues a considerable clinical concern. The aim of this study is to evaluate attention and emotion regulation across radiotherapy period and the possible effects of complementary alternative medicine (CAM). METHODS: Fifty-seven patients with unilateral breast cancer underwent surgery and systemic chemotherapy before participating in this double-blind randomized study. Two thirds were given CAM (n = 38) while the rest received placebo (carrier only, n = 19). Patients' attention and anxiety were physiologically tested at baseline, 2 and 4 weeks during the radiation period as well as 1-month after the end of radiation session. RESULTS: Both groups showed similar levels of anxiety with no significant differences at baseline nor post-radiotherapy. Long-term significant recovery of attention performance was observed in the CAM patients, accompanied by a similar tendency in anxiety level, measured by the eye-blink probability. CONCLUSIONS: This study physiologically validates the attention impairment reported among breast cancer survivors; also, it depicted a beneficial late-effect of a routine CAM on attention dysregulation. The suggested non-invasive physiological measures can physiologically monitor patients' psychological and cognitive well-being as well as evaluate the beneficial effect of CAM in breast cancer patients by assessing their coping ability to support the treatment plan. Thus, the results have potential clinical implications on patients' and survivors' quality of life. TRIAL REGISTRATION: NIH, NCT02890316. Registered July 2016, http://www.ClinicalTrials.gov.

High resolution behavioral and neural activity representation using a geometrical approach.

Available tools for recording neuronal activity are limited and reductive due to massive data arising from high-frequency measurements. We have developed a method that utilizes variance within the physiological activity and includes all data points per measurement. Data is expressed geometrically in a physiologically meaningful manner, to represent a precise and detailed view of the recorded neural activity. The recorded raw data from any pair of electrodes was plotted and following a covariance calculation, an eigenvalues and chi-square distribution were used to define the ellipse which bounds 95% of the raw data. We validated our method by correlating specific behavioral observation and physiological activity with behavioral tasks that require similar body movement but potentially involve significantly different neuronal activity. Graphical representation of telemetrically recorded data generates a scatter plot with distinct elliptic geometrical properties that clearly and significantly correlated with behavior. Our reproducible approach improves on existing methods by allowing a dynamic, accurate and comprehensive correlate using an intuitive output. Long-term, it may serve as the basis for advanced machine learning applications and animal-based artificial intelligence models aimed at predicting or characterizing behavior.

Feline cognitive dysfunction as a model for Alzheimer's disease in the research of CBD as a potential treatment-a narrative review.

With the improvement in modern medicine, the world's human and feline (Felis catus, the domestic cat) population is aging. As the population grows older, there is an increase of age-related diseases, such as Alzheimer's disease in humans and feline cognitive dysfunction in felines, which shares many similarities with Alzheimer's disease. They both result in cognitive decline and lack effective treatments. In light of their pathological similarities, both occur at old age, and as domestic cats share the human environment and risk factors (cats are considered an indicator to the effect of environmental contaminants on humans as they share exposures and diseases), cats have the potential to be a spontaneous model for Alzheimer's disease. Classic animal models in many cases fail to predict the results in humans, and a natural model can lead to better prediction of results, thus being both time and cost-effective. The feline disease can be researched in trials that could be simultaneously clinical trials for cats and preclinical trials for humans, also referred to as reverse translational medicine. As both maladies lack effective medical intervention, new potential treatments are merited. Cannabidiol (CBD) is a promising agent that may improve the life of these patients, as it was shown to potentially treat several of the pathologies found in both conditions. yet there is a need for further research in order to establish the benefits and safety of CBD to both human and feline patients.

Developmental effects of environmental enrichment on selective and auditory sustained attention.

Environmental enrichment (EE) has been used as a positive manipulation in different disease models. However, there is conflicting evidence reported in the literature about the effects of EE. Additionally, the time period that would be most beneficial in implementing environmental enrichment as an intervention is not clear. Our study aimed to systematically compare the prenatal, juvenile, mid-adolescence, and adulthood developmental trajectory to further the understanding of enriched environment's effects on selective and auditory sustained attention, corresponding to behavioral (conceived) and physiological-reflexive (non-conceived) measures. Rats were exposed for 21 days to enriched environment during various developmental periods and compared to age-matched controls. All groups were tested for long-term effects (at postnatal day 120 and onward) on selective and sustained attention. We found that the exposure to enriched environment during mid-adolescence has yielded the most significant and long-term pattern of effects, including selective and auditory sustained attention performance, increased foraging-like behavior and a significant decrease in corticosterone level. Similarly, the exposure to EE at juvenile period improved selective attention, increased foraging-like behavior, and reduced anxiety levels as reflected in the open field as well as in low corticosterone levels. These results specify a crucial period along the developmental trajectory for applying environmental enrichment. Mid-adolescence is suggested, in future basic and translational studies, as the sensitive time period that induces the most beneficial and long-term effects of EE on attention. The current findings suggest that the exposure to EE during mid-adolescence should be further considered and studied as behavioral alternative intervention, or as adjuvant behavioral therapy, aimed to decrease the probability to develop ADHD in post-adolescence period. This suggestion is highly relevant due to the debate regarding the pros and cons of screens usage (e.g. Facebook, online games, etc.) during early life that decreases environmental enrichment, especially, direct social interaction.

A probabilistic model of startle response reveals opposite effects of acute versus chronic Methylphenidate treatment.

BACKGROUND: The startle response is considered as the major physio-behavioral indication of anxiety in health and disease conditions. However, due to different protocols of stimulation and measurement, the magnitude as well as the appearance of the startle response is inconsistent. NEW METHOD: We postulate that the startle probability and not merely the amplitude may bare information that will form a consistent physiological measure of anxiety. RESULTS: To examine the proof-of-concept of our suggested probability model, we evaluated the effects of acute (single) versus chronic (14 days) MPH administration on both startle amplitude and probability. We found that both acute and chronic MPH administration has yielded similar effects on startle amplitude. However, acute MPH increased the startle's probability while chronic MPH decreased it. Next, we evaluated the effects of acute versus chronic stress on the startle's parameters and found a complementary effect. Explicitly, acute stress increased the startle's probability while chronic stress increased the startle amplitude. In contrast, enriched environment had no significant effects. Finally, to further validate the probability measure, we show that Midazolam had significant anxiolytic effects. In the second part, we investigated the acoustic startle response parameters (e.g. background noise and pulse duration), to better understand the interplay between these parameters and the startle amplitude versus probability. CONCLUSIONS: We show that the probabilistic element of the startle response does not only point to deeper physiologic relationships but may also serve as "hidden variables" congruent but not entirely identical to the commonly researched amplitude of the startle response.

ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment.

d-serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover. The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating d-serine levels. Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of d-serine metabolism. ASCT1 is a major d-serine uptake system in astrocytes and can also export l-serine via heteroexchange, supplying neurons with the substrate for d-serine synthesis. ASCT1-KO mice display lower levels of brain d-serine along with higher levels of l-alanine, l-threonine, and glycine. Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes. Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of d-serine vs. glycine in mediating NMDA receptor activity. In vivo microdialysis demonstrated lower levels of extracellular d-serine in ASCT1-KO mice, confirming altered d-serine metabolism. These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations. ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations.

Use of information and communication technologies among individuals with and without serious mental illness.

Growing interest surrounds the use ofinformation and communication technologies (ICTs) for mental-health-related purposes, yet little is known about rates of ICT use among the psychiatric population and those with severe mental illness. This study examines ICT accessibility among the psychiatric population, focusing on serious and non-serious mental illness (SMI and non-SMI). Patients (N = 427) from all service branches of the Psychiatry Department at Emek Medical Centerwere recruited orally or through advertisement. Responders completed a self-report survey regarding accessibility and use of ICTs (i.e., computer, internet, Facebook, mobile phone, smartphone). Results revealed that 59.3% of respondents used computers, 77.3% used the internet, 92.7% owned a mobile phone, 67.9% owned a smartphone, and 63% used Facebook. Over half of participants who used ICTs reported doing so at least once per day. SMI and non-SMI respondents differed significantly in their use and access to a computer, the internet, Facebook, and smartphones. Results suggest that mental illness is not a barrier to using and accessing technology; however, when differentiating between SMI and non-SMI, illness severity is a barrier to potential ICT utilization. These results may encourage policy makers to design ICTs that suit the needs of individuals with SMI.

Altered Volatile Organic Compound Profile in Transgenic Rats Bearing A53T Mutation of Human α-Synuclein: Comparison with Dopaminergic and Serotonergic Denervation.

Early diagnosis of Parkinson's disease (PD) is of great importance due its progressive phenotype. Neuroprotective drugs could potentially slow down disease progression if used at early stages. Previously, we have reported an altered content of volatile organic compounds (VOCs) in the breath of rats following a 50% reduction in striatal dopamine (DA) content induced by 6-hydroxydopamine. We now report on the difference in the breath-print and content of VOCs between rats with mild and severe lesions of DA neurons, serotonergic neuronal lesions, and transgenic (Tg) rats carrying the PD-producing A53T mutation of the SNCA (α-synuclein) gene. The Tg rats had an increased content of 3-octen-1-ol and 4-chloro-3-methyl phenol in blood, while in brain tissue, hexanal, hexanol, and 2,3-octanedione were present in controls but absent in Tg rats. Levels of 1-heptyl-2-methyl cyclopropane were increased in brain tissue of Tg rats. The data confirm the potential of breath analysis for detection of human idiosyncratic as well as autosomal dominant PD.

Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain.

d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity.