The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex.

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.

Toxicidad de memantina intravítrea en retina de conejos / Intravitreal memantine retinal toxicity in rabbits

OBJETIVO: Valorar histopatológicamente si existe toxicidad en la retina de conejos, posterior a la aplicación intravítrea de memantina. MÉTODOS: Se utilizaron 16 ojos de 16 conejos raza Nueva Zelanda de 3 kg, divididos en 4 grupos de 4 conejos cada uno. Al grupo A se le aplicó una dosis de 70 ng/ml de memantina intravítrea, al grupo B se le aplicó una dosis de 150 ng/ml de memantina intravítrea, al grupo C se le aplicó una dosis de 400 ng/ml de memantina intravítrea, y al grupo D se le aplicó 1 ml de solución salina balanceada. Se enucleó el ojo inyectado en la mitad de cada grupo a los 15 días, y el resto del grupo se enucleó a los 30 días posterior a la inyección. Posterior a la enucleación, cada ojo fue colocado en formaldehido al 10%. Se realizó análisis histopatológico a cada uno de los ojos enucleados. Los animales fueron tratados de acuerdo a los estatutos de la Association for Research on Vision and Ophthalmology (ARVO). RESULTADOS: Los grupos A, B y D no presentaron alteraciones histopatológicas tras 15 y 30 días de enucleación. El grupo C presentó alteración a nivel de la capa de fotorreceptores a los 15 y 30 días posterior a la enucleación. CONCLUSIONES: La memantina intravítrea a dosis de 70 mg/dl y 150 mg/dl no es tóxica a nivel estructural en la retina. La memantina a dosis de 400 mg/dl es tóxica a nivel estructural en la retina. La memantina podría ser considerada en el futuro para el tratamiento de distrofias de retina. Diversos estudios deberán ser realizados al respecto

OBJECTIVE: To histologically evaluate whether the intravitreal application of memantine produces retinal toxicity in rabbits. METHODS: A cross-sectional design, experimental, descriptive study was performed on 16 eyes of 16 New Zealand rabbits of 3 kg, divided in 4 groups of 4 rabbits. A dose of 70 ng/ml of intravitreal memantine was administered in Group A, a dose of 150 ng/ml in Group B, a dose of 400 ng/ml in Group C, and Group D received 1 ml of balanced salt solution. The injected eye of half of each group was enucleated 15 days after the injection, and the rest within 30 days after injection. Following enucleation, each eye was placed in 10% formaldehyde. Histopathological analysis was performed on all enucleated eyes. The animals were treated according to the guidelines of the Association for Research on Vision and Ophthalmology (ARVO). RESULTS: Groups A, B and D did not show any histopathological changes after their enucleation at 15 and 30 days. Group C showed changes in the photoreceptor layer after enucleation at 15 and 30 days. CONCLUSIONS: In our study, it was observed that memantine concentrations at 70 ng/ml and 150 ng/ml are safe when administered intravitreally; however, doses of 400 ng/ml produced retinal structural changes. This research should continue to assess its clinical usefulness

Degeneración cerebelosa paraneoplásica asociada a anticuerpos anti-Ma2 / Paraneoplastic cerebellar degeneration associated with anti-Ma2 antibodies

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Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice.

The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.

Interacción de los receptores NMDA - 5-HT6 en la investigación preclínica de las alteraciones cognitivas relacionadas con la esquizofrenia / Interaction of nmda AND 5-HT6 receptors in the preclinical investigation of schizophrenia-related cognitive changes

Diversos antagonistas del receptor N-metil-D-aspartato (RNMDA) como la fenciclidina o la ketamina estudiados en roedores han permitido inducir alteraciones cognitivas similares a las observadas en la esquizofrenia. Casualmente, uno de los receptores a serotonina, el 5-HT6, ha cobrado interés en la búsqueda de nuevos fármacos con propiedades procognitivas. Con la finalidad de comprender mejor la interacción de ambos receptores (NMDA y 5-HT6) en la regulación cognitiva se realizó una revisión exhaustiva en la literatura. Varios estudios con esquemas agudos o subcrónicos de los antagonistas NMDA en roedores fueron evaluados en distintas pruebas, en donde se encontró deterioro cognitivo. Fue común que el esquema agudo de diversos fármacos serotoninérgicos 5-HT6 revirtiera el deterioro cognitivo inducido por la administración previa de los antagonistas del RNMDA. Por el contrario y sorprendentemente, la inyección aguda y combinada tanto de los antagonistas NMDA como de los fármacos serotoninérgicos 5-HT6 lograron fortalecer la memoria. El esquema subcrónico de los antagonistas NMDA representa el modelo más integrador para el estudio de las alteraciones cognitivas asociadas a la esquizofrenia. Aunque el deterioro y el efecto procognitivo mediados por estos receptores pudieran ser explicados mediante la regulación conjunta que ejercen ambos receptores sobre la liberación de distintos neurotransmisores como el glutamato, es una situación compleja que se requiere continuar investigando para fundamentar mejor estas ideas (AU)

Diverse antagonists of the NMDA receptor studied in rodents, such as phencyclidine or ketamine, have enabled researchers to induce cognitive changes similar to those found in schizophrenia. Interestingly, one of the serotonin receptors, 5-HT6, has attracted much attention for the development of new drugs with pro-cognitive properties. With the aim of better understanding the interaction of both NMDA and 5-HT6 in cognitive regulation, an exhaustive review of the literature was carried out. Various studies have found cognitive impairment, evaluated in rodents using different tests, after applying acute or sub-chronic schemes of NMDA antagonists. An acute scheme of applying different serotogenic 5-HT6 receptors has often reversed the cognitive impairment induced by the previous administration of NMDA antagonists. Surprisingly, an acute injection of a combination of suboptimal doses of NMDA and 5-HT6 antagonists resulted in strengthening memory. The sub-chronic scheme of NMDA antagonists represents the most reliable model for the study of cognitive changes associated with schizophrenia. Cognitive impairment, as well as a pro-cognitive effect mediated by NMDA and 5-HT6, may be explained by a joint regulation of these receptors to modulate the release of distinct neurotransmitters, such as glutamate. This represents a complex interaction that requires ongoing research to clarify the mechanisms at play (AU)

Effects of maternal enflurane exposure on NR2B expression in the hippocampus of their offspring

This work aims to study the pathogenesis of learning and memory impairment in offspring rats resulting from maternal enflurane anesthesia by focusing on the expression of the N-methyl-d-aspartic acid receptor subunit 2B (NR2B) in the hippocampus of the offspring. Thirty female Sprague-Dawley rats were randomly divided into three groups: control (C group), 4 h enflurane exposure (E1 group), and 8 h enflurane exposure (E2 group) groups. Eight to ten days after the initiation of pregnancy, rats from the E1 and E2 groups were allowed to inhale 1.7% enflurane in 2 L/min oxygen for 4 h and 8 h, respectively. Rats from the C group were allowed to inhale 2 L/min of oxygen only. The Morris water maze was used to assay the learning and memory function of the offspring on postnatal days 20 and 30. RT-PCR and immunohistochemistry assays were then used to measure the mRNA levels and protein expression of NR2B, respectively. Relative to offspring rats from the C group, those from the E1 and E2 groups exhibited longer escape latencies, lesser number of crossings over the platform, and less time spent in the target quadrant in the spatial exploration test (P < 0.05). In addition, the mRNA and protein expression levels of NR2B in the hippocampus of offspring rats in the E1 and E2 groups were down-regulated (P < 0.05). No significant differences between the E1 and E2 groups were observed (P > 0.05) in terms of mRNA levels and protein expression of NR2B. The cognitive function of the offspring is impaired when maternal rats are exposed to enflurane during early pregnancy. A possible mechanism of this effect is related to the down-regulation of NR2B expression.

Este trabalho objetiva o estudo da patogênese de deficiência no aprendizado e memória de prole de ratos resultante da anestesia maternal por enflurano, por meio da expressão da subunidade 2B do receptor do ácidoN-metil-D-aspártico (NR2B) no hipocampo dos filhotes. Dividiram-se, aleatoriamente, 30 fêmeas de ratos Sprague-Dawley em três grupos: controle (grupo C), exposição ao enflurano por 4 h (grupo E1) e por 8 h (grupo E2). De oito a 10 dias após o início da gravidez, os ratos dos grupos E1 e E2 inalaram enflurano 1,7% em 2 L/min de oxigênio, por 4 h e 8 h, respectivamente. Ratos do grupo C inalaram apenas 2 L/min de oxigênio. O labirinto de água de Morris foi empregado para analisar as funções de aprendizado e memória da cria em 20 e 30 dias após o nascimento. Utilizaram-se ensaios de RT-PCR e de imuno-histoquímica para medir os níveis de mRNA e expressão da proteína do NR2B, respectivamente. Em comparação com os ratos controle do grupo C, aqueles dos grupos E1 e E2 exibiram latências de escape mais longas, menor número de travessias na plataforma e menos tempo gasto no quadrante alvo no teste de exploração espacial (P < 0,05). Adicionalmente, os níveis de expressão de mRNA e de proteína do NR2B no hipocampo dos filhotes nos grupos E1 e E2 estavam reduzidos (P < 0,05). Não se observaram diferenças significativas entre os grupos E1 e E2 (P < 0,05) quanto aos níveis de mRNA e à expressão de proteína de NR2B. A função cognitiva dos filhotes é prejudicada quando as mães são expostas ao enflurano durante o início da gravidez. O mecanismo possível para esse efeito está relacionado à diminuição na expressão de NR2B.

The bioanalytical molecular pharmacology of the N-methyl-D-aspartate (NMDA) receptor nexus and the oxygen-responsive transcription factor HIF-1α: putative mechanisms and regulatory pathways unravel the intimate hypoxia connection.

Hypoxia-mediated regulation of N-methyl-D-aspartate (NMDA) receptor (NMDAR) is phenomenal. NMDAR is no doubt an intriguing paradoxical glutamate receptor (GluR) with versatile actions. GluRs play a pivotal role in brain physiology and pathophysiology under ischemia and oxygen deprivation, where NMDARs are major contributors. Activation of NMDARs is closely associated with the kinetics of intracellular calcium (Ca(2+)) release, a main player in neuronal cell death in the central nervous system (CNS). However, CNS exposure to hypoxia modulates NMDAR/Ca(2+) physiology in such a way that there is a small window of operating neuroprotection, rather than the classical neuroinjurious effects manifested upon Ca(2+) release. The NMDAR connection with hypoxia-inducible factor-1α (HIF-1α), a transcription factor considered master regulator of oxygen sensing mechanisms, is not well established in the CNS. However, scanning the literature yielded a wealth of NMDAR/hypoxia connection but that with HIF-1α is not prominent. It is worth mentioning that this is not a comprehensive review on the effect of hypoxia on NMDAR physiology, rather this synopsis sheds light on the putative mechanisms involving HIF-1α and NMDAR regulation. Understanding the evidence of this intimate connection and its ramifications may bear potential applications in unraveling hypoxia-mediated injury, neuronal cell death and, most importantly, adaptive, neuroprotective mechanisms to oxygen deprivation.

Enantioselective two-dimensional high-performance liquid chromatographic determination of N-methyl-D-aspartic acid and its analogues in mammals and bivalves.

A validated and fully automated chiral 2D-HPLC system was developed for the simultaneous determination of N-methyl-d-aspartic acid (NMDA) analogues by combining a long microbore-monolithic ODS column (0.53 mm i.d.× 1,000 mm) and narrowbore-enantioselective columns (1.5mm i.d.×150 or 250 mm). The target analytes, enantiomers of N-methylaspartic acid (NMA) and N-methylglutamic acid (NMG), were precolumn-derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and detected by their fluorescence. The values of the lower limit of quantification for these enantiomers were 2.5 fmol. In the tissues and plasma of rats, neither NMA nor NMG were detected. On the other hand, in the mantle and foot of Scapharca broughtonii, a large amount of NMDA was present (170.1 and 43.5 nmol/g), and the enantiomers of NMG were also observed. Meretrix lusoria contained NMDA (29.3 nmol/g) and NMLG (13.8 nmol/g), and Ruditapes philippinarum contained only NMLG (2.6 nmol/g). The obtained results were confirmed using three different enantioselective columns and also using a 2D-HPLC-MS/MS system. These results indicated that neuroactive d-amino acid, NMDA, and its analogues were present in animals, and their physiological significance is expected to be clarified.

Effects of ozone and ozone/peroxide on trace organic contaminants and NDMA in drinking water and water reuse applications.

An ozone and ozone/peroxide oxidation process was evaluated at pilot scale for trace organic contaminant (TOrC) mitigation and NDMA formation in both drinking water and water reuse applications. A reverse osmosis (RO) pilot was also evaluated as part of the water reuse treatment train. Ozone/peroxide showed lower electrical energy per order of removal (EEO) values for TOrCs in surface water treatment, but the addition of hydrogen peroxide increased EEO values during wastewater treatment. TOrC oxidation was correlated to changes in UV(254) absorbance and fluorescence offering a surrogate model for predicting contaminant removal. A decrease in N-nitrosodimethylamine (NDMA) formation potential (after chloramination) was observed after treatment with ozone and ozone/peroxide. However, during spiking experiments with surface water, ozone/peroxide achieved limited destruction of NDMA, while in wastewaters net direct formation of NDMA of 6-33 ng/L was observed after either ozone or ozone/peroxide treatment. Once formed during ozonation, NDMA passed through the subsequent RO membranes, which highlights the significance of the potential for direct NDMA formation during oxidation in reuse applications.

HPLC methods for determination of D-aspartate and N-methyl-D-aspartate.

D-Amino acids are stereoisomers or optical isomers of naturally occurring L-amino acids and thus possess the same chemical structure, but may differ in their biological/physiological properties. Until a half century ago, D-amino acids had been considered to be unnatural substances found only in microorganisms. However, improvements in analytical instruments and methods have revealed that D-amino acids are present in invertebrates and vertebrates, including humans, and that they possess important physiological functions. D-Aspartate (D-Asp) and its methylated form N-methyl-D-aspartate (NMDA) possess neuroendocrine properties in many species. Several methods have been developed for determination of D- and L-enantiomers of amino acids by high performance liquid chromatography (HPLC). We report here improved HPLC methods for the specific determination of D-Asp and NMDA in biological tissues.

Antitussive effects of memantine in guinea pigs.

BACKGROUND: The treatment of cough is a significant clinical unmet need because there is little evidence that current therapies are effective. Based on evidence supporting a role for N-methyl D-aspartate receptors (NMDARs) in cough, we hypothesized that memantine, a low-affinity, uncompetitive NMDAR channel blocker in routine use for the treatment of Alzheimer disease, could be an effective, well-tolerated, antitussive therapy. The aim of this study was to establish preclinical evidence that memantine has antitussive effects. METHODS: We studied the influence of memantine on experimentally induced coughing in response to citric acid and bradykinin inhalation in guinea pigs. We also compared the potency and efficacy of memantine as an antitussive to other NMDAR antagonists, dextromethorphan and ketamine, and to the γ-aminobutyric acid class B receptor agonist baclofen. RESULTS: Compared with control subjects, 10 mg/kg memantine significantly reduced the cumulative number of coughs evoked by both citric acid (median, 24.0 [interquartile range (IQR), 13.0-25.5] vs 1.5 [IQR, 0.3-10.3] coughs; P = .012) and bradykinin aerosols (median, 16.0 [IQR, 9.5-18.5] vs 0.0 [IQR, 0-0.75] coughs; P = .002). Memantine 10 mg/kg produced a similar reduction in the cumulative number of coughs to baclofen 3 mg/kg and demonstrated comparatively greater cough suppression than 30 mg/kg dextromethorphan or 30 mg/kg ketamine. This dose of memantine produced no sedative or respiratory depressive effects. CONCLUSIONS: This study illustrates that memantine has marked antitussive effects in guinea pigs, most likely mediated through NMDAR channel blockade. Memantine, therefore, has the potential to be a safe, effective, and well-tolerated antitussive agent.

Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA)-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716) during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

Determination of D-aspartate N-methyltransferase activity in the starfish by direct analysis of N-methyl-D-aspartate with high-performance liquid chromatography.

We describe a method for the detection and quantification of D-aspartate N-methyltransferase activity. The enzyme catalyzes the S-adenosyl-L-methionine-dependent N-methylation of D-aspartate to form N-methyl-D-aspartate (NMDA). NMDA is detected directly by high-performance liquid chromatography (HPLC) of their (+)- and/or (-)-1-(9-fluorenyl)ethyl chloroformate fluorescent derivatives. The NMDA production in the assay mixture is linearly proportional to the incubation time and the amount of tissue homogenate. Using a 10 min incubation time, the method allows detection of the enzyme activity below 10 fmol/min. It can be used to analyze kinetic behavior and to quantify the enzyme from a wide variety of organisms.

Nuevo caso de encefalitis antirreceptor de NMDA sin tumor asociado / A novel case of anti-NMDA receptor encephalitis with no associated tumour

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Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system.

BACKGROUND: Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the Xenopus laevis tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits. RESULTS: Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-alpha on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-alpha resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-alpha treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-alpha-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures. CONCLUSIONS: Taken together our data are consistent with a model in which TNF-alpha causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.

HPLC determination of acidic D-amino acids and their N-methyl derivatives in biological tissues.

D-Aspartate (D-Asp) and N-methyl-D-aspartate (NMDA) occur in the neuroendocrine systems of vertebrates and invertebrates, where they play a role in hormone release and synthesis, neurotransmission, and memory and learning. N-methyl-d-glutamate (NMDG) has also been detected in marine bivalves. Several methods have been used to detect these amino acids, but they require pretreatment of tissue samples with o-phthaldialdehyde (OPA) to remove primary amino acids that interfere with the detection of NMDA and NMDG. We report here a one-step derivatization procedure with the chiral reagent N-alpha-(5-fluoro-2,4-dinitrophenyl)-(D or L)-valine amide, FDNP-Val-NH2, a close analog of Marfey's reagent but with better resolution and higher molar absorptivity. The diastereomers formed were separated by HPLC on an ODS-Hypersil column eluted with TFA/water-TFA/MeCN. UV absorption at 340 nm permitted detection levels as low as 5-10 pmol. D-Asp, NMDA and NMDG peaks were not obscured by other primary or secondary amino acids; hence pretreatment of tissues with OPA was not required. This method is highly reliable and fast (less than 40 min HPLC run). Using this method, we detected D-Asp, NMDA and NMDG in several biological tissues (octopus brain, optical lobe and bucchal mass; foot and mantle of the mollusk Scapharca broughtonii), confirming the results of other researchers.

N-methyl-D-aspartic acid (NMDA) in the nervous system of the amphioxus Branchiostoma lanceolatum.

BACKGROUND: NMDA (N-methyl-D-aspartic acid) is a widely known agonist for a class of glutamate receptors, the NMDA type. Synthetic NMDA elicits very strong activity for the induction of hypothalamic factors and hypophyseal hormones in mammals. Moreover, endogenous NMDA has been found in rat, where it has a role in the induction of GnRH (Gonadotropin Releasing Hormone) in the hypothalamus, and of LH (Luteinizing Hormone) and PRL (Prolactin) in the pituitary gland. RESULTS: In this study we show evidence for the occurrence of endogenous NMDA in the amphioxus Branchiostoma lanceolatum. A relatively high concentration of NMDA occurs in the nervous system of this species (3.08 +/- 0.37 nmol/g tissue in the nerve cord and 10.52 +/- 1.41 nmol/g tissue in the cephalic vesicle). As in rat, in amphioxus NMDA is also biosynthesized from D-aspartic acid (D-Asp) by a NMDA synthase (also called D-aspartate methyl transferase). CONCLUSION: Given the simplicity of the amphioxus nervous and endocrine systems compared to mammalian, the discovery of NMDA in this protochordate is important to gain insights into the role of endogenous NMDA in the nervous and endocrine systems of metazoans and particularly in the chordate lineage.

Lesion Location in Depression Post Traumatic Brain Injury Using Magnetic Resonance Spectroscopy: Preliminary Results from a Pilot Study

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Objective: To determine the metabolic status of the brain in post traumatic brain injury(TBI) depression using proton magnetic resonance spectroscopy (MRS). DESIGN: Case-control study including 5 TBI depressed subjects and 5 age matched non-TBI non-depressed controls. Methods: Metabolic status was assessed using proton MRS. Ratios of N-acetylaspartate (NAA), choline (Cho) and total creatine (Cr) were calculated in frontal cortex, basal ganglia and thalamus. Results: NAA/Cho or NAA/Cr ratios were significantly reduced in the TBI depressed group compared to controls in frontal cortex, basal ganglia and thalamus. Conclusion: Reduced levels of NAA in frontal regions, basal ganglia and thalamus in TBI depression suggest neuronal damage or dysfunction which may be a associated with the primary brain injury or with depressed mood (AU)

D-aspartate and reproductive activity in sheep.

D-aspartic acid (D-Asp) has been isolated from neuroendocrine tissues of many invertebrates and vertebrates. Recently, it has been demonstrated that this D-amino acid may be converted to N-methyl-D-aspartic acid (NMDA), a neuromodulator associated with sexual activity. In this study, we determined D-Asp and NMDA concentrations in endocrine glands and other tissues in ewes after D-Asp administration and in controls. We also evaluated the effects of d-Asp administration on the reproductive activity of ewes by determining either progesterone concentrations or LH pulses in the presence or absence of estradiol benzoate. The pineal gland showed the highest natural content of D-Asp (1.47+/-0.22 micromol/g tissue), whereas the pituitary gland had the highest capability to store d-Asp, with a peak value (9.7+/-0.81 micromol/g tissue) 6 h after its administration. NMDA increased sharply 12 h following D-Asp administration, reaching values three times higher than the baseline in both the pituitary and brain. D-Asp was quickly adsorbed after subcutaneous administration, with a peak in plasma levels 2 h after administration and a return to baseline values after 6 h. D-Asp administration achieved a significant (P < 0.001) increase in LH values with respect to estradiol or estradiol + D-Asp treatments. d-Asp treatment once or twice a week did not successfully drive acyclic ewes into reproductive activity. In conclusion, the results obtained in this study demonstrated that D-Asp is endogenously present in sheep tissues and electively stored in endocrine glands and brain after its administration. NMDA and LH increase following D-Asp administration suggesting a role of this D-amino acid in the reproductive activity of sheep.

Extracellular taurine in the substantia nigra: taurine-glutamate interaction.

Taurine has been proposed as an inhibitory transmitter in the substantia nigra (SN), but the mechanisms involved in its release and uptake remain practically unexplored. We studied the extracellular pool of taurine in the rat's SN by using microdialysis methods, paying particular attention to the taurine-glutamate (GLU) interaction. Extracellular taurine increased after cell depolarization with high-K(+) in a Ca(2+)-dependent manner, being modified by the local perfusion of GLU, GLU receptor agonists, and zinc. Nigral administration of taurine increased the extracellular concentration of gamma-aminobutyric acid (GABA) and GLU, the transmitters of the two main inputs of the SN. The modification of the glial metabolism with fluocitrate and L-methionine sulfoximine also changed the extracellular concentration of taurine. The complex regulation of the extracellular pool of taurine, its interaction with GABA and GLU, and the involvement of glial cells in its regulation suggest a volume transmission role for taurine in the SN.