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A previous study of substituent effects on the photocleavage of 1-acyl-7-nitroindolines has been extended to examine the effects of electron-donating and electron-withdrawing substituents. 1-Acetyl-4,5-methylenedioxy-7-nitroindoline 7 was inert to 350 nm irradiation, reinforcing an earlier finding that excessive electron-donation by substituents can divert the excited state into non-productive pathways. By contrast, the 1-acetyl-5,7-dinitro- and 1-acetyl-4-methoxy-5,7-dinitroindolines 8 and 9 respectively both showed improved photolysis efficiency in aqueous solution compared to the 1-acyl-4-methoxy-7-nitro compound 2. Unlike 2, both 8 and 9 gave mixed photoproducts, the corresponding dinitroindolines and the 5-nitro-7-nitrosoindoles. These results are interpreted in terms of a previous mechanistic study. Investigation of the 4-methoxy-5,7-dinitroindoline conjugate of L-glutamate 18 showed that the stoichiometry of glutamate release upon photolysis was only 65–77% of the theoretical value, suggesting that photolysis of these dinitro compounds may involve pathways other than the clean photolysis previously observed for mono-nitro compounds such as 2.

MDMA (N-methyl-3,4-methylenedioxyamphetamine) produces a discriminative stimulus (DS) effect in animals, but attempts to completely block this action with selective neurotransmitter antagonists have not been very successful. Biochemically, MDMA can increase synaptic levels of serotonin, dopamine, and norepinephrine that, conceivably, might interact with multiple populations or subpopulations of neurotransmitter receptors. The present study attempted to antagonize the DS effects of MDMA using the nonselective agents clozapine, cyproheptadine, and pizotyline. An extensive and comparative radioligand binding profile was also obtained for the latter two agents. The purported antagonists were administered in combination with the training dose of MDMA to groups of Sprague-Dawley rats trained to discriminate 1.5 mg/kg of MDMA from saline vehicle in a standard two-lever operant paradigm using a VI-15s schedule of reinforcement. Clozapine was without effect at the doses evaluated, and cyproheptadine only partially attenuated MDMA-appropriate responding. In contrast, pizotyline (AD50=2.5 mg/kg), in combination with the MDMA training dose, resulted in a dose related decrease in percent drug-appropriate responding to saline levels. In a separate group of animals trained to discriminate the structurally-related agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) from vehicle, pretreatment with pizotyline also resulted in a substantial decrease in drug-appropriate responding. The results with cyproheptadine and pizotyline in the binding assays confirmed that these agents display high affinity for multiple subpopulations of serotonergic, dopaminergic, adrenergic, histaminergic, and cholinergic receptors. The overall results of the present investigation indicate that pizotyline, which is clinically available in some countries, might be of clinical utility in the treatment of MDMA overdose.

This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.

Introduction: Epidemiologic studies have suggested that consumption of cold water fish oils may have some protective function against depression. This proposition is supported by a series of biochemical and pharmacologic studies that have suggested that fatty acids may modulate neurotransmitter metabolism and cell signal transduction in humans and that abnormalities in fatty acid and eicosanoid metabolism may play a causal role in depression. Aware of the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, we decided to conduct an open-label add-on trial of eicosapentaenoic acid (EPA) in bipolar depression. Method: Twelve bipolar I outpatients with depressive symptoms diagnosed by DSM-IV were treated with 1.5 to 2 g/day of the omega-3 fatty acid EPA for up to 6 months. The study was conducted between September 2001 and January 2003. Results: Eight of the 10 patients who completed at least 1 month of follow-up achieved a 50% or greater reduction in Hamilton Rating Scale for Depression scores within 1 month. No patients developed hypomania or manic symptoms. No significant side effects were reported. Limitations: This study is limited both by the open-label design and by the small sample size. As in all previous reported studies, patients in this study were treated in an outpatient setting, so that the most severely depressed bipolar patients (requiring hospitalization) are not represented. Conclusions: Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.

Docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) are important structural components of the central nervous system. These fatty acids are transferred across the placenta, and are accumulated in the brain and other organs during fetal development. Depletion of 22:6n-3 from the retina and brain results in reduced visual function and learning deficits: these may involve critical roles of 22:6n-3 in membrane-dependent signaling pathways and neurotransmitter metabolism. Transfer of 22:6n-3 across the placenta involves specific binding and transfer proteins that facilitate higher concentrations of 22:6n-3 and 20:4n-6, but lower linoleic acid (18:2n-6) in fetal compared with maternal plasma, or in the breast-fed or formula-fed infant. However, human and animal studies both demonstrate that maternal diet impacts fetal 22:6n-3 and 20:4n-6 accretion. After birth, parenteral lipid, human milk and infant formula feeding all result in a marked decrease in plasma 22:6n-3 and 20:4n-6 and an increase in 18:2n-6. Estimation of fetal tissue fatty acid accretion suggests that current preterm infant feeds are unlikely to meet in utero rates of 22:6n-3 accretion. Consideration needs to be given to whether fetal plasma 22:6n-3 and 20:4n-6 enrichment and the low 18:2n-6 facilitates accretion of 22:6n-3 and 20:4n-6 in developing tissues.

Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B with Ki values in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or with trans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (Ki = 3 μm) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 “gate” is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.

In the mouse, neurotransmitter metabolism can be regulated by modulation of the synthesis of pyridoxal 5'-phosphate and failure to maintain pyridoxal phosphate (PLP) levels results in epilepsy. This study of five patients with neonatal epileptic encephalopathy suggests that the same is true in man. Cerebrospinal fluid and urine analyses indicated reduced activity of aromatic L-amino acid decarboxylase and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5'-phosphate oxidase (PNPO). Sequencing of the PNPO gene identified homozygous missense, splice site and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1g>a) and stop codon (X262Q) mutations were null activity mutations and that the missense mutation (R229W) markedly reduced pyridox(am)ine phosphate oxidase activity. Maintenance of optimal PLP levels in the brain may be important in many neurological disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon).

We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.7 +/- 1.3 micromol min(-1) (mean +/-s.e.m.) in the placebo trial and 2.5 +/- 1.0 micromol min(-1) in the glucose trial (P < 0.05 compared to rest, not different across trials). At rest, CSF ammonia was below the detection limit of 2 microm in all subjects, but it increased to 5.3 +/- 1.1 microm following exercise with glucose, and further to 16.1 +/- 3.3 microm after the placebo trial (P < 0.05). Correlations were established between both the cerebral uptake (r2 = 0.87; P < 0.05) and the CSF concentration (r2 = 0.72; P < 0.05) and the arterial ammonia level and, in addition, a weaker correlation (r2 = 0.37; P < 0.05) was established between perceived exertion and CSF ammonia at the end of exercise. The results let us suggest that during prolonged exercise the cerebral uptake and accumulation of ammonia may provoke fatigue, e.g. by affecting neurotransmitter metabolism.

The metabolic turnover of nicotinic ACh receptors (AChR) at the neuromuscular synapse is regulated over a tenfold range by innervation status, muscle electrical activity and neural agrin, but the downstream effector of such changes has not been defined. The AChR-associated protein rapsyn is essential for forming AChR clusters during development. Here, rapsyn was tagged with enhanced green fluorescent protein (EGFP) to begin to probe its influence at the adult synapse. In C2 myotubes, rapsyn–EGFP participated with AChR in agrin-induced AChR cluster formation. When electroporated into the tibialis anterior muscle of young adult mice, rapsyn–EGFP accumulated in discrete subcellular structures, many of which colocalized with Golgi markers, consistent with the idea that rapsyn assembles with AChR in the exocytic pathway. Rapsyn–EGFP also targeted directly to the postsynaptic membrane where it occupied previously vacant rapsyn binding sites, thereby increasing the rapsyn to AChR ratio. At endplates displaying rapsyn–EGFP, the metabolic turnover of AChR (labelled with rhodamine-α-bungarotoxin) was slowed. Thus, the metabolic half-life of receptors at the synapse may be modulated by local changes in the subsynaptic ratio of rapsyn to AChR.

Introduction: Research into prostate development and function is mainly carried out in rats and guinea pigs. While these animals have proven to be good models of human prostate function, their use is limited when compared with what could be achieved using the various currently available gene knockout mice. This study aimed to ascertain whether the mouse prostate was a viable model for studying human prostate function. Methods: Sections from mouse prostate glands were histochemically processed to visualise the neurotransmitters and receptors present. Isolated organ bath studies were conducted in Krebs–Henseleit solution at 37 °C to delineate the physiological mechanisms involved in contractility. Results: Positive histochemical staining for noradrenaline and acetylcholinesterase (AChE) was observed in the fibromuscular stroma. AChE-positive staining was also observed in epithelial cells lining prostatic acini. Immunoreactivity to P2X1 and P2X7 purinoceptors was observed in the fibromuscular stroma and immunoreactivity to P2X4 purinoceptors in the glandular epithelium. Positive immunostaining for neuropeptide Y, big endothelin, calcitonin gene-related peptide (CGRP), substance P, and neurokinin A was observed in the fibromuscular stroma. Frequency-response curves (1.0 ms pulse duration, 60 V, 0.1–20 Hz) to electrical field stimulation yielded frequency-dependent contractions that were attenuated by tetrodotoxin (P

The definition of neurotransmitter receptors expressed by individual neuronal phenotypes is essential for our understanding of integrated neural regulation. We report here a single-neuron strategy using green fluorescent protein (GFP)-promoter transgenic mice and oligonucleotide microarrays that has enabled us to provide a qualitative profile of the neurotransmitter receptors expressed by the gonadotropin- releasing hormone (GnRH) neurons, critical for the neural regulation of fertility. Acute brain slices were prepared from adult female GnRH-GFP transgenic mice and single GnRH neurons identified and patched. The contents of GnRH neurons underwent reverse transcription and cDNA amplification using the switch mechanism at the 5' end of RNA templates system, and hybridization to mouse gene oligonucleotide arrays. Fifty different neurotransmitter receptor subunit mRNAs were detected in GnRH neurons. Many of the classical amino acid and aminergic receptors were present in addition to 14 distinct, and in most cases novel, neuropeptidergic receptor signaling families. Four of the latter were selected for functional validation with gramicidin-perforated patch-clamp electrophysiology. Galanin, GnRH and neuromedin B were all found to exert direct depolarizing actions upon GnRH neurons whereas somatostatin induced a potent hyperpolarizing response. These studies demonstrate a relatively straightforward approach for transcriptome profiling of specific neuronal phenotypes. The stimulatory actions of GnRH and galanin upon GnRH neurons found here indicate that positive ultrashort feedback loops exist among the GnRH neuronal population.

Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a two-compartment mathematical model of neurotransmitter metabolism. Rats (n= 23) were infused simultaneously with14C-bicarbonate and [1-13C]glucose for up to 1 hr. The14C and13C labeling of glutamate, glutamine, and aspartate was measured at five time points in tissue extracts using scintillation counting and13C nuclear magnetic resonance of the chromatographically separated amino acids. The isotopic13C enrichment of glutamate and glutamine was different, suggesting significant rates of glial metabolism compared with the glutamate-glutamine cycle. Modeling the13C-labeling time courses alone and with14C confirmed significant glial TCA cycle activity (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(V_{\mathrm{PDH}}^{(\mathrm{g})},{\sim}0.5\) \end{document}μmol · gm-1· min-1) relative to the glutamate-glutamine cycle (VNT) (∼0.5-0.6 μmol · gm-1· min-1). The glial TCA cycle rate was ∼30% of total TCA cycle activity. A high pyruvate carboxylase rate (VPC, ∼0.14-0.18 μmol · gm-1· min-1) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same13C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.

Monoamine oxidase (MAO), discovered in the 1930s by Balschko, is one of the most important enzymes in neurotransmitter metabolism. MAO inhibitors have played a major role in our understanding of the functional roles of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) neurotransmission in the CNS. Nonselective MAO inhibitors were studied as antidepressants in the late 1950s and 1960s, although their usefulness was limited by their potential to cause a “cheese reaction.” The cheese reaction is associated with the presence of tyramine and other indirectly acting sympathomimetic amines present in food (e.g., cheeses) and alcoholic drinks (e.g., wine). MAO metabolizes most such amines. As a consequence of MAO inhibition, tyramine is not metabolized, which enables it to enter the circulatory system and induce a release of NE from peripheral adrenergic neurons (figure 1). The consequence can be a severe cardiovascular response that leads to hypertensive crisis. Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese reaction, and NE release and metabolism after MAO-A inhibition. The demonstration that MAO was not a single enzyme but existed in several forms was strengthened by the observation that the MAO inhibitor clorgyline could differentiate between two forms of MAO.1,2⇓ Johnson2 termed these enzymes type A and type B. The MAO-A enzyme is responsible for the deamination of NA and 5-HT, whereas the MAO-B enzyme metabolizes phenylethylamine (PEA). Tyramine and dopamine are equally well metabolized by both MAO-A and MAO-B (table). 3,4⇓ View this table: Table Some natural and synthetic substrates of monoamine oxidase The presence of MAO-A and MAO-B in postmortem human brains suggested the possibility of developing MAO inhibitors directed at each subtype for the treatment of diseases such as PD and depression.5,6⇓ l-Deprenyl (selegiline), a selective irreversible MAO-B inhibitor, was the first drug shown to …

Although the existence of thalamostriatal projections has long been known, the role(s) of this system in the basal ganglia circuitry remains poorly characterized. The intralaminar and ventral motor nuclei are the main sources of thalamic inputs to the striatum. This review emphasizes the high degree of anatomical and functional specificity of basal ganglia-thalamostriatal projections and discusses various aspects of the synaptic connectivity and neurochemical features that differentiate this glutamate system from the corticostriatal network. It also discusses the importance of thalamostriatal projections from the caudal intralaminar nuclei in the process of attentional orientation. A major task of future studies is to characterize the role(s) of corticostriatal and thalamostriatal pathways in regulating basal ganglia activity in normal and pathological conditions.

Wnt proteins are intercellular signals that regulate various aspects of animal development. In Caenorhabditis elegans, mutations in lin-17, a Frizzled-class Wnt receptor, and in lin-18 affect cell fate patterning in the P7.p vulval lineage. We found that lin-18 encodes a member of the Ryk/Derailed family of tyrosine kinase-related receptors, recently found to function as Wnt receptors. Members of this family have nonactive kinase domains. The LIN-18 kinase domain is dispensable for LIN-18 function, while the Wnt binding WIF domain is required. We also found that Wnt proteins LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning. Genetic interactions indicate that LIN-17 and LIN-18 function independently of each other in parallel pathways, and different ligands display different receptor specificities. Thus, two independent Wnt signaling pathways, one employing a Ryk receptor and the other a Frizzled receptor, function in parallel to regulate cell fate patterning in the C. elegans vulva.

The cause or causes of Tourette's syndrome (TS) remain unknown. Functional imaging studies have evaluated several implicated neurotransmitter systems and focused predominantly on the frequency or severity of tics. The results have been inconclusive and frequently contradictory with little light shed on pathogenetic mechanisms. However, metabolic derangements have been demonstrated within regions of the basal ganglia, limbic system and sensori-motor cortex and are in keeping with the concept of TS as both a motor and behavioral disorder. TS has long been regarded an involuntary movement disorder. However, many patients have stated that without the premonitory sensation, there would be no tics. For this reason, it has been suggested that the premonitory urge may be considered the involuntary component of TS and the performance of the tic merely a voluntary response. Future studies are needed to differentiate functional changes relating to urge from those associated with the performance of tics and tic suppression.

The brain uses glucose as its primary fuel. Cerebral metabolism of glucose requires transport through the blood-brain barrier, glycolytic conversion to pyruvate, metabolism via the tricarboxylic acid cycle and ultimately oxidation to carbon dioxide and water for full provision of adenosine triphosphate (ATP) and its high-energy equivalents. When deprived of glucose, the brain becomes dysfunctional or can be even permanently damaged. Glucose is stored as glycogen within astrocytes with potential importance for tolerance of hypoglycemia. Glycogen may also be important for the metabolic response to somatosensory stimulation and coupling of blood flow and cellular metabolism. Uncontrolled diabetes has a variety of adverse effects upon brain metabolism and function. Many aspects of function that affect the brain may be indirectly linked to cerebral glucose metabolism. Neurotransmitter metabolism, cerebral blood flow, blood-brain barrier and microvascular function may all be affected to varying degrees by either hypoglycemia or uncontrolled diabetes mellitus.

The effects of edible mushroom Mycoleptodonoides aitchisonii on the synthesis of nerve growth factor (NGF) and neurotransmitter metabolism in rat brain were examined in Wistar strain rats fed a controlled diet for 14 days. Then each brain was dissected to detect the levels of neurotransmitters and NGF in various regions. Dopamine concentration in the cerebral cortex was 1.5-fold significantly increased in the M. aitchisonii feeding group than the control group. However, NGF concentration of the M. aitchisonii feeding was significantly low. NGF concentration in this remaining area of brain from where the cerebral cortex, striatum, hippocampus, cerebellum, hypothalamus and amygdala were removed was significantly higher in the M. aitchisonii feeding. At the same time, in the striatum, the dopamine metabolite DOPAC was significantly increased in the M. aitchisonii feeding. Thereafter, we measured dopamine release from striatal slices using aqueous extract of M. aitchisonii, there was an enhancing effect on dopamine release. These results suggested that M. aitchisonii has enhancing effect on the synthesis of NGF and catecholamine metabolites in the rat brain.

In the brain, catabolism of the branched-chain amino acids (BCAAs) provides nitrogen for the synthesis of glutamate and glutamine. Glutamate is formed through transfer of an amino group from BCAA to α-ketoglutarate in reaction catalyzed by branched-chain aminotransferases (BCAT). There are two isozymes of BCAT: cytosolic BCATc, which is found in the nervous system, ovary, and placenta, and mitochondrial BCATm, which is found in all organs except rat liver. In cell culture systems, BCATc is found only in neurons and developing oligodendrocytes, whereas BCATm is the isoform in astroglia. In this study, we used immunohistochemistry to examine the distribution of BCATc in the rat brain, focusing on the well-known neural architecture of the cerebellum and hippocampus. We show that BCATc is expressed only in neurons in the adult rat brain. In glutamatergic neurons such as granule cells of the cerebellar cortex and of the dentate gyrus, BCATc is localized to axons and nerve terminals. In contrast, in GABAergic neurons such as cerebellar Purkinje cells and hippocampal pyramidal basket cells, BCATc is concentrated in cell bodies. A common function for BCATc in these neurotransmitter systems may be to modulate amounts of glutamate available either for release as neurotransmitter or for use as precursor for synthesis of GABA. Particularly striking in our findings is the strong expression of BCATc in the mossy fiber pathway of the hippocampal formation. This result is discussed in light of the effectiveness of the anticonvulsant drug gabapentin, which is a specific inhibitor of BCATc. J. Comp. Neurol. 477:360–370, 2004. © 2004 Wiley-Liss, Inc.

1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (+/-)piperidine-3-sulfonic acid (PSA) inhibited [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.

The detrimental effects of lead poisoning have been well known since ancient times, but some of the most severe consequences of exposure to this metal have only been described recently. Lead [Pb(II)] affects the higher functions of the central nervous system and undermines brain growth, preventing the correct development of cognitive and behavioral functions. As an established neurotoxin, Pb(II) crosses the blood-brain barrier rapidly and concentrates in the brain. The mechanisms of lead neurotoxicity are complex and still not fully understood, but recent findings recognized that both Ca(II) dependent proteins and neurotransmitters receptors represent significant targets for Pb(II). In particular, acute and chronic exposure to lead would predominantly affect two specific protein complexes: protein kinase C and the N-methyl-D-aspartate subtype of glutamate receptor. These protein complexes are deeply involved in learning and cognitive functions and are also thought to interact significantly with each other to mediate these functions. This review outlines the most recent hypotheses and evidences that link lead poisoning to impairment of these protein functions, as well as the in vitro experimental approaches that are most likely to provide information on basic mechanicistic processes.

Taste consumption activates the extracellular responsive kinases 1-2 (ERK1-2) and the transcription factor Elk-1 in the insular cortex (IC) of the behaving rat. ERKs activation, an obligatory step for the encoding of long- but not short-term memory, was shown to be regulated by multiple neurotransmitter systems in the IC. Here I show, by the use of local microinfusions of pharmacological agents into the IC of the behaving rat, that a set of similar systems is required for the taste-induced activation of Elk-1. N-Methyl-D-aspartate (NMDA), glutamate metabotropic (mGlu), ionotropic AMPA/kainate (AMPA), muscarinic, and dopaminergic receptors, which all contribute to the acquisition of taste memory, are also responsible for Elk-1 activation. However, blockade of the beta-adrenergic transmission does not affect Elk-1 activation. I also show that the basal level of Elk-1 activation in cortex is mainly maintained by GABAergic transmission. Thus, the formation of taste memory triggers the activation of Elk-1 in the IC of the behaving rat via selected neurotransmitter and neuromodulatory systems.

Here we describe a novel mechanism for plasma membrane insertion of the delta opioid receptor (DOR). In small dorsal root ganglion neurons, only low levels of DORs are present on the cell surface, in contrast to high levels of intracellular DORs mainly associated with vesicles containing calcitonin gene-related peptide (CGRP). Activation of surface DORs caused Ca(2+) release from IP(3)-sensitive stores and Ca(2+) entry, resulting in a slow and long-lasting exocytosis, DOR insertion, and CGRP release. In contrast, membrane depolarization or activation of vanilloid and P2Y(1) receptors induced a rapid DOR insertion. Thus, DOR activation induces a Ca(2+)-dependent insertion of DORs that is coupled to a release of excitatory neuropeptides, suggesting that treatment of inflammatory pain should include blockade of DORs.

This report describes a computer model of a “column” in the cat motor cortex. The model includes two layers of two-segment pyramidal neurons with two groups of inhibitory interneurons in each layer, which selectively control the somatic and dendritic segments of the pyramidal cells. In this model, neurons include active sodium, calcium, and several types of potassium currents. Excitatory connections between neurons are of the AMPA and NMDA types, while collateral connections between neurons of the upper layer are mainly of the NMDA type; connections between neurons in the lower layer are of the AMPA type. All inhibitory connections are of the GABAA type. The model reproduces the main neuronal processes seen in the cat motor cortex during performance of an operant movement. Pyramidal neurons of the upper layer generate primary and secondary responses to external stimuli. As in real experiments, secondary NMDA-dependent responses appear when GABAA inhibition is weakened and disappear when stimulation is increased; these properties of secondary responses are only reproduced when NMDA receptors are located in the terminals of collateral connections. Using only rapid NMDA-independent connections, neurons in the lower layer generate a slow bell-shaped wave of excitation (a “motor command”), which is formed by sequential activation of neurons with dendritic trees of different sizes.

The pyruvate dehydrogenase complex (PDHc) is a member of a family of multienzyme complexes that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the physiologically irreversible decarboxylation of various 2-oxoacid substrates to their corresponding acyl-CoA derivatives, NADH and CO2. PDHc deficiency is a metabolic disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration that vary with age and gender. In this review, we aim to discuss the relationship between occurrence of epilepsy and PDHc deficiency associated with the pyruvate dehydrogenase complex (E1α subunit (PDHA1) and E1β subunit (PDHB)) and PDH phosphatase (PDP) deficiency. PDHc plays a crucial role in the aerobic carbohydrate metabolism and regulates the use of carbohydrate as the source of oxidative energy. In severe PDHc deficiency, the energy deficit impairs brain development in utero resulting in physiological and structural changes in the brain that contributes to the subsequent onset of epileptogenesis. Epileptogenesis in PDHc deficiency is linked to energy failure and abnormal neurotransmitter metabolism that progressively alters neuronal excitability. This metabolic blockage might be restricted via inclusion of ketogenic diet that is broken up by β-oxidation and directly converting it to acetyl-CoA, and thereby improving the patient's health condition. Genetic counseling is essential as PDHA1 deficiency is X-linked. The demonstration of the X-chromosome localization of PDHA1 resolved a number of questions concerning the variable phenotype displayed by patients with E1 deficiency. Most patients show a broad range of neurological abnormalities, with the severity showing some dependence on the nature of the mutation in the Elα gene, while PDHB and PDH phosphatase (PDP) deficiencies are of autosomal recessive inheritance. However, in females, the disorder is further complicated by the pattern of X-chromosome inactivation, i.e., unfavorable lyonization. Furthermore research should focus on epileptogenic animal models; this might pave a new way toward identification of the pathophysiology of this challenging disorder.

Recent studies have shown that Wnt signaling molecules and the occurrence and development of Alzheimer's disease are closely related. Wnt protein secretion by autocrine or located next to the cell membrane receptor binding, activation of intracellular signaling pathways to regulate expression of target genes of cell proliferation during embryonic development, differentiation, migration, polarity and apoptosis has played an important role. The pathological mechanism of Alzheimer's disease involves inherited, environmental and immunological factors. Strong evidence exists that Wnt signaling pathway is closely related to the pathological process of Alzheimer's disease. There is also evidence that Wnt signaling pathway plays a crucial effect on the proliferation of neural stem cells. To review the relationship between pathological process of Alzheimer's disease and Wnt signaling pathway and effects of Wnt signaling on proliferation and differentiation of neural stem cells, providing theoretical evidence for treatment of Alzheimer's disease. Theoretical Introduction of Alzheimer's Disease Alzheimer's disease (Alzheimer's disease AD) is more common in people over the age 60, Alzheimer's disease is the onset before the age of 65, and senile dementia refers to over 65 years of onset. AD etiology is not clear, family history is a risk factor for AD, but also may be related to a number of diseases related to the immune system. Ap accumulate a large number of nerve cells and Wnt ligands will Ap direct binding, may also be combined with the cell membrane Fz receptors results in inhibition of Wnt signaling pathway, sometimes they exhibit relatively activation, inhibition of abnormal activation and signal causes cellular signal transduction direction changes, is blocked to intracellular signals transduced cells. Its pathogenesis is currently elusive, the following theory as genetic mutation theory, theory of cholinergic nerve abnormalities, prisoners ingot amyloid, genetics, said the doctrine of central neurotransmitter metabolism, cytoskeletal change doctrine, the doctrine of immune abnormalities, free radicals and apoptosis in doctrine and excitatory amino acid toxicity theory from different angles, etc. are proved with Alzheimer's disease have a certain relevance. AR doctrine which dominates the hypothesis that AR prisoners ingot amyloid protein precursor (APP) cleavage is the main component of the brain cortex and hippocampus A Ll region form a large number of patients with senile plaques (senile plaque, SP) of It caused pathological changes of AD, leading to neurofibrillary tangles (neurofibrillary tangles, NFT) formation, as well as diffuse intracellular protein Tau River, vascular injury and dementia form (1) .

Recently, two extrastriate visual areas on the posterior fusiform gyrus, areas FG1 and FG2, were identified based on cytoarchitectonical criteria (Caspers et al. in Brain Struct Funct 218:511-526, 2013a). They are located within the object-related ventral visual stream at the transition between early and higher-order (category-specific) visual areas. FG2 has a topographical position which is best comparable to the face or visual word-form recognition area. However, the precise function of FG2 is presently unknown. Since transmitter receptors are key molecules of neurotransmission, we analysed the regional and laminar distribution of 15 different receptor binding sites by means of quantitative in vitro receptor autoradiography. Significant differences between receptor densities of both areas were found for NMDA, GABAB, M3, nicotinic α4/β2 and 5-HT1A receptors as well as for GABAA associated benzodiazepine binding sites. These results support the cytoarchitectonic segregation of FG1 and FG2 into two distinct cortical areas. In addition, principal component and hierarchical cluster analyses of the multireceptor data of both fusiform areas and 24 visual, auditory, somatosensory and multimodal association areas not only revealed the typical receptor architectonic characteristics of visual areas for FG1 and FG2, but also suggest their putative function as object recognition regions due to the similarity of their receptor fingerprints with those of areas of the ventral visual stream. Furthermore, FG1 and FG2 build a cluster with the multimodal association areas of the inferior parietal lobule. This underlines their hierarchically high position in the visual system of the human cerebral cortex.

Autism spectrum disorder (ASD) is multifactorial and complex condition, with a marked genetic influence, as evidenced by the high heritability (around 80–90 %). Additionally, both common and rare genetic variants have an influence on the etiology and development. Several genetic syndromes are described in ASD, and they are present in approximately 10 % of cases. Different genetic approaches are described in studies with ASD samples. Linkage studies mainly identify regions in chromosomes 2 and 7 which are involved in ASD. Genetic association studies, which aim to identify genes or genomic regions influencing ASD, involve the analysis of candidate genes or genome scan. The genes analyzed in these studies encode components related to neurotransmitter metabolism, neural migration, neuronal cell adhesion, apoptosis, and cell proliferation. Other methodologies have been used to complement genetic investigations, for example, exome and copy number variation (CNV) studies. Epigenetic studies indicate an important environmental influence on these disorders. The genetic evaluation of all patients with ASD is now required due to recent advances in knowledge regarding the genetic factors involved in the etiology of autism. Definitions of key terms and concepts used throughout this chapter are presented in Fig. 3.1.

In present study, we investigated the role of hypoxia inducible factor-1 (HIF-1) in regulation of taurine transport through the blood-brain barrier (BBB) under high glucose condition using TR-BBB cells as an in vitro model of BBB. Treatment with high glucose (25 mM) for 48 h induced HIF-1α and VEGF expression, and decreased [3H]taurine uptake in TR-BBB cells. Also, high glucose condition reduced taurine transporter (TauT) mRNA and protein levels. In addition, pre-treatment with HIF-1 inducer, cobalt chloride in TR-BBB cells decreased TAUT expression. Glucose-induced TauT down-regulation could be reversed by inhibition of HIF-1 and VEGF using several HIF-1 and VEGF inhibitors. Also, both HIF-1 inhibitors and VEGF inhibitors induced the decrease of [3H]taurine uptake caused by high glucose. In conclusion, taurine transport through the BBB can be down-regulated by high glucose, which is mediated to induction of HIF-1 and VEGF. Therefore, we suggest that the inhibitors of HIF-1 and VEGF could have the beneficial effects on hyperglycemia by up-regulation of taurine contents in brain.

There is substantial interest in the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine in psychiatric research because it exerts acute psychotomimetic and rapid antidepressant effects in rodents and humans. Here, we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of interleukin 4, tumor necrosis factor alpha, and fibroblast growth factor 9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This involved changes in signaling kinases and proteases such as protein kinase C beta, neurochondrin (NCDN), calcineurin, extracellular signal-regulated kinsase 1 (ERK1), and mammalian target of rapamycin (MTOR). Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (mitochondrial aspartate aminotransferase, catechol O-methyl transferase, synaptic vesicle endo-/exocytosis (vesicle fusing ATPase (NSF), synapsin 1 (SYN1), syndapin-1 (PACN1)). Consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I, prohibitin (PHB) and neurofilament proteins (neurofilament light chain and alpha-internexin (AINX)). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamines mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder.

Neurotransmitter disorders are a group of inherited neurometabolic diseases attributable to disturbances of neurotransmitter metabolism. Classical neurotransmitter pathways involve amino acids (such as γ-aminobutyric acid [GABA], glycine, and glutamate), cholinergic transmission, monoamines (dopamine, serotonin, noradrenaline, and adrenaline), and purines. Other molecules such as neuropeptides, ion channels, and diverse neuromodulators are also involved in neurotransmission mechanisms and thus in the pathophysiology of neurological disorders. In this chapter we will focus on biogenic amines, GABA and its cofactors defects, since they are the most common groups of human neurotransmitter diseases. The biogenic amines regulate brain functions such as movement, behavior, emotions, temperature, blood pressure and endocrine secretion. Disorders of monoamines include levodopa-related movement disorders and early complex encephalopathies. GABAergic transmission regulates epileptic mechanisms, cognition, behavior, and arousal level. Clinical presentations include epileptic encephalopathies, intellectual disability, behavioral disturbances, and episodes of lethargy. Most neurotransmitter disorders are treatable and require the study of cerebrospinal fluid metabolites for diagnosis.

Recent data indicate that there are multiple mechanisms mediating fast and slow synaptic excitation in the enteric nervous system. However, these data also suggest that both the neurotransmitters and the receptors mediating fast and slow synaptic transmission in the myenteric plexus are organized in a polarity- (ascending versus descending) and pathway- (excitatory versus inhibitory) specific manner.

The density of transmitter receptors varies between different locations in the human cerebral cortex. We hypothesized that this variation may reflect the cyto- and myeloarchitectonical as well as the functional organisation of the cortex. We compared data from different imaging modalities (postmortem studies: cyto- and myeloarchitecture, quantitative in vitro receptor autoradiography; in vivo studies: PET receptor neuroimaging) in order to test our hypothesis. The regional and laminar distribution of the densities of numerous receptor types representing all classical transmitter systems as well as the adenosine system are visualized and measured in different cortical areas. The receptor distribution patterns segregate motor, primary sensory, unimodal sensory, multimodal association and other functionally identified cortical areas from each other. Areas of similar function show similar receptor fingerprints and differ from those with other properties. Thus, receptor distribution patterns reflect an organisational structure strictly correlated with the architectonics and functions of the human cerebral cortex.

Most advances in addiction treatment to date have addressed the physical dependence and withdrawal that accompany addiction to some drugs of abuse. In contrast, it has proven more difficult to develop medications that effectively treat drug craving and relapse, the core features of addictive disorders. Current efforts focus on developing medications that prevent a drug from getting to its protein target, that mimic drug action and thereby partially alleviate drug craving, or that affect the addiction process per se. The latter approach is the most speculative, but also the most promising in terms of translating basic knowledge of addiction into clinical progress.

Synapse formation and stabilization in the vertebrate central nervous system is a dynamic process, requiring bi-directional communication between pre- and postsynaptic partners. Numerous mechanisms coordinate where and when synapses are made in the developing brain. This review discusses cellular and activity-dependent mechanisms that control the development of synaptic connectivity.

Neurotoxicity due to excessive brain manganese (Mn) can occur due to environmental (air pollution, soil, water) and/ or metabolic aberrations (decreased biliary excretion). Manganese is associated with oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional [Mn], it is likely that in pathological conditions it can reach 100-500 microM. Amino acid (e.g. aspartate, glutamate, taurine), as well as divalent metal (e.g. zinc, manganese) concentrations are regulated by astrocytes in the brain. Recently, it has been reported that cultured rat primary astrocytes exposed to Mn displayed decreased glutamate uptake, thereby, increasing the excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn employs in terms of glutamate metabolism is unknown, a primary goal of this study was to link altered glutamate uptake in Mn exposed astrocytes to alterations in glutamate transporter message. Further, we wanted to examine the gene expression of metallothionein (MT) and taurine transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40% in accordance with a 48% decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine uptake was unaffected by Mn exposure even though tau-T mRNA increased by 123%. MT mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism, although this was not examined. These data show that glutamate and taurine transport in Mn exposed astrocytes are temporally different.

Volatile anesthetics (VAs) disrupt nervous system function by an ill-defined mechanism with no known specific antagonists. During the course of characterizing the response of the nematode C. elegans to VAs, we discovered that a C. elegans pheromone antagonizes the VA halothane. Acute exposure to pheromone rendered wild-type C. elegans resistant to clinical concentrations of halothane, increasing the EC50 from 0.43 ± 0.03 to 0.90 ± 0.02. C. elegans mutants that disrupt the function of sensory neurons required for the action of the previously characterized dauer pheromone blocked pheromone-induced resistance (Pir) to halothane. Pheromone preparations from loss-of-function mutants of daf-22, a gene required for dauer pheromone production, lacked the halothane-resistance activity, suggesting that dauer and Pir pheromone are identical. However, the pathways for pheromone’s effects on dauer formation and VA action were not identical. Not all mutations that alter dauer formation affected the Pir phenotype. Further, mutations in genes not known to be involved in dauer formation completely blocked Pir, including those altering signaling through the G proteins Goα and Gqα. A model in which sensory neurons transduce the pheromone activity through antagonistic Go and Gq pathways, modulating VA action against neurotransmitter release machinery, is proposed.

Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.

Manganese (Mn) is an essential nutrient. However, a longitudinal study showed that exposure to Mn containing welding fumes under federal safety limits may cause a dose-dependent progression of Parkinsonism. Excess Mn causes neurotoxicity, however the underlying molecular mechanism remains unclear. Disrupted polyamine metabolism with increased putrescine levels was observed in suicidal cohorts and also occurs in multiple neurologic disorders, but no information is available on the possible effects of Mn on polyamine metabolism. To test the hypothesis that increased Mn causes increased putrescine and altered polyamine metabolism, human SH-SY5Y neuroblastoma cells were treated with MnCl2 (0,1,5,10,50,100μM for 5 hr; n=9/condition). Results showed that cellular Mn measured was representative of normal to pathological range (6 to 49 ng/mg protein) in the human brain. Putrescine and other untargeted metabolites were analyzed by liquid chromatography-ultra high-resolution mass spectrometry followed by metabolome-wide association study (MWAS) of putrescine. Results showed that cellular Mn caused a dose dependent increase in putrescine content (3.2 nmol/mg protein to 4.5 nmol/mg protein; p

Idiopathic epilepsies, which account for up to 40% of all epilepsies, are mainly caused by genetic factors. Most idiopathic epilepsies are due to oligogenic or multifactorial rather than monogenetic inheritance. Nevertheless, most of what is known today about the molecular genetics of idiopathic epilepsies has been found by analysing large families with rare monogenetic forms of the disease. For the first time, gene defects can be linked to certain epilepsies. Mutations in the CHRNA4 or CHRNB subunits of the neuronal nicotinic acetylcholine receptor lead to familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been found to cause benign familial neonatal convulsions. The voltage-gated sodium channel subunits SCN1B, SCN1A and SCN2A as well as the GABRG2 subunit of the GABA(A) receptor are involved in the pathology of the newly described syndrome generalized epilepsy with febrile seizures plus. These rare monogenetic epilepsies can serve as models for further genetic analysis of the common forms of idiopathic epilepsies.

In recent years, improvement in diagnostic techniques has led to better recognition of "disorders of cortical development". These disorders constitute a significant cause of epilepsy, mental retardation, developmental delay and neurological deficits in childhood, and may also contribute to the pathogenesis of psychological and neurodegenerative diseases in adults. Hitherto, however, few systematic studies of the human fetal cortex have been performed, and little is known about the ontogenetic processes of the neocortex in man. The aim of the study is to establish an understanding of the developmental events that occur in the second and third trimesters of gestation, by investigating the biochemical patterns of development of the human neocortex during this period. The temporal and spatial patterns of expression of the neuronal markers gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), dopamine beta hydroxylase (DBH), dopamine receptor DR1 and synaptophysin, as well as the glial cell markers glial fibrillary acidic protein (GFAP), S100B and excitatory amino acid transporter protein GLT-1 are delineated in the fetal cortex using immunohistochemistry. Results of this study showed that different neuronal and glial cell proteins follow different developmental patterns and many show inter- or intra-regional variations in expression. Details of these patterns are described and discussed. The early expression of these proteins suggests that they play important roles in the developmental processes of cell proliferation, migration and differentiation. Both neurotransmitters and glial cell proteins probably function outside the confines of synapses in the fetal brain, as paracrine/autocrine factors. Early developmental events seem to be dictated by an innate programme, whereas late events may be more susceptible to extrinsic influences. It is hoped that knowledge of the normal developmental process can lead to better understanding of the causes and mechanisms of "disorders of cortical development", and to better treatments.

1. It has been discussed for over 100 years whether short-term memory (STM) is separate from, or just an early phase of, long-term memory (LTM). The only way to solve this dilemma is to find out at least one treatment that blocks STM while keeping LTM intact for the same task in the same animal. 2. The effect of a large number of treatments infused into the hippocampus, amygdala, and entorhinal, posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM, and again at 24 h for LTM. The treatments were given after training. 3. Eleven different treatments blocked STM without affecting LTM. Eighteen treatments affected the two memory types differentially, either blocking or enhancing LTM alone. Thus, STM is separate from, and parallel to the first hours of processing of, LTM of that task. 4. The mechanisms of STM are different from those of LTM. The former do not include gene expression or protein synthesis; the latter include a double peak of cAMP-dependent protein kinase activity, accompanied by the phosphorylation of CREB, and both gene expression and protein synthesis. 5. Possible cellular and molecular events that do not require mRNA or protein synthesis should account for STM. These might include a hyperactivation of glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins that participate in cell addition.

Faced with stress and acute instances, brain cells trigger neuroinflammation and increase inflam-mation response and can cause cell damage, cell death and thereby functional insufficiencies, behavioral disorders and autonomic imbalances. Cytokines that play an important role in inflamma-tory processes affect neurotransmitter metabolism, neuroendocrine functions and synaptic plasticity. It has been proven that inflammatory activity increases in depression. Proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α along with acute phase reactants increase in depression. If the inflammatory response becomes chronic and cannot be balanced, inflammation and cytokines may cause behavioral symptoms and neuropsychiatric disorders such as major depression and anxiety disorders. In this article, the changes that occur in inflammatory processes in depressive disorder will be summarized; the effects of pharmacologic and psychotherapeutic approaches on these changes will be reviewed., Beyin hücreleri stres ve akut olaylar karşısında nöroinflamasyonu tetikleyerek ve inflamasyon yanıtını arttırarak hücre hasarına, ölümüne ve dolayısıyla fonksiyonel yetersizliklere, davranışsal bozukluklara ve otonomik dengesizliklere yol açabilmektedir. İnflamatuvar süreçlerde önemli rol oynayan sitokinler nörotransmitter metabolizması, nöroendokrin işlevler ve sinaptik plastisiteyi etkilemektedir. Depresyonda inflamatuvar aktivitenin artmış olduğu kanıtlanmıştır. Depresyonda interlökin (IL)-1, IL-6 ve tümör nekroz faktör (TNF)-α gibi proinflamatuvar sitokinler ve akut faz reaktanları artmaktadır. Psikososyal stresörlere yanıt olarak ortaya çıkan bu immun değişiklikler geçicidir ve anti-inflamatuvar mekanizmalarla dengelenmektedir. Bununla birlikte, inflamatuvar yanıt kronikleşirse ya da dengelenemezse inflamasyon ve sitokinler davranışsal belirtilere ve major depresyon, anksiyete bozuklukları gibi nöropsikiyatrik hastalıklara yol açabilmektedir. Bu yazıda, major depresif bozuklukta inflamatuvar süreçlerde meydana gelen değişiklikler özetlenecek, farmakolojik ve psikoterapötik yaklaşımların bu değişiklikler üzerine etkileri gözden geçirilmiştir.

The relationship between depression and immunity has been widely discussed. Cytokines, such as TNF-α, play an important role in immune system; these cytokines interact with virtually every pathophysiologic domain relevant to depression, including neurotransmitter metabolism, neuroendocrine function, and synaptic plasticity. Antibodies have also been implicated in the pathophysiology of depression. The association between decreased serotonin levels and excessive glutamatergic activity forms the first biochemical basis for cytokine-induced depression. Cytokines and antibodies (anti-ribosomal-P and anti-N-methyl-D-aspartate receptor antibodies) are deeply related to pathogenesis of neurodevelopmental disorders, especially depression. Tumor necrosis factor alpha (TNF-α) may underlie the mechanism of depression by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters and the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion. In the last 20 years since the initial reports of neural-immune interactions in depression, studies have shown a clear association between activation of the immune system mediated by proinflammatory cytokines. Genes encoding cytokines are highly polymorphic and single nucleotide polymorphisms, associated with increased or reduced cytokine production, have been described. To date, there are only few studies that investigated the relationship between depression and proinflammatory cytokines in patients with autoimmune diseases. Although an associative link between neuroinflammation and mood disorders is widely accepted, further studies are necessary to establish the cause-effect relationship. In this paper, we review the role of cytokines, focusing on TNF-α and antibodies in the depression and hypothesize how TNF-α may underlie and mediate the inflammatory process depression in patients with autoimmune disease.

Aims: The human branched-chain aminotransferase proteins (hBCATm and hBCATc) are regulated through oxidation and S-nitrosation. However, it remains unknown whether they share common redox characteristics to enzymes such as protein disulfide isomerase (PDI) in terms of regulating cellular repair and protein misfolding. Results: Here, similar to PDI, the hBCAT proteins showed dithiol-disulfide isomerase activity that was mediated through an S-glutathionylated mechanism. Site-directed mutagenesis of the active thiols of the CXXC motif demonstrates that they are fundamental to optimal protein folding. Far Western analysis indicated that both hBCAT proteins can associate with PDI. Co-immunoprecipitation studies demonstrated that hBCATm directly binds to PDI in IMR-32 cells and the human brain. Electron and confocal microscopy validated the expression of PDI in mitochondria (using Mia40 as a mitochondrial control), where both PDI and Mia40 were found to be co-localized with hBCATm. Under conditions of oxidative stress, this interaction is decreased, suggesting that the proposed chaperone role for hBCATm may be perturbed. Moreover, immunohistochemistry studies show that PDI and hBCAT are expressed in the same neuronal and endothelial cells of the vasculature of the human brain, supporting a physiological role for this binding. Innovation: This study identifies a novel redox role for hBCAT and confirms that hBCATm differentially binds to PDI under cellular stress. Conclusion: These studies indicate that hBCAT may play a role in the stress response of the cell as a novel redox chaperone, which, if compromised, may result in protein misfolding, creating aggregates as a key feature in neurodegenerative conditions such as Alzheimer's disease. Antioxid. Redox Signal. 20, 2497–2513.

International audience; Neuropsychiatric symptoms are frequent in obesity. In addition to their substantial economic and health impact, these symptoms significantly interfere with the quality of life and social function of obese individuals. While the pathophysiological mechanisms underlying obesity-related neuropsychiatric symptoms are still under investigation and remain to be clearly identified, there is increasing evidence for a role of inflammatory processes. Obesity is characterized by a chronic low-grade inflammatory state that is likely to influence neuropsychiatric status given the well-known and highly documented effects of inflammation on brain activity/function and behavior. This hypothesis is supported by recent findings emanating from clinical investigations in obese subjects and from experimentations conducted in animal models of obesity. These studies converge to show that obesity-related inflammatory processes, originating either from the adipose tissue or gut microbiota environment, spread to the brain where they lead to substantial changes in neurocircuitry, neuroendocrine activity, neurotransmitter metabolism and activity, and neurogenesis. Together, these alterations contribute to shape the propitious bases for the development of obesity-related neuropsychiatric comorbidities.

Synapses store information by long-lasting modifications of their structure and molecular composition, but the precise chronology of these changes has not been studied at single-synapse resolution in real time. Here we describe the spatiotemporal reorganization of postsynaptic substructures during long-term potentiation (LTP) at individual dendritic spines. Proteins translocated to the spine in four distinct patterns through three sequential phases. In the initial phase, the actin cytoskeleton was rapidly remodeled while active cofilin was massively transported to the spine. In the stabilization phase, cofilin formed a stable complex with F-actin, was persistently retained at the spine, and consolidated spine expansion. In contrast, the postsynaptic density (PSD) was independently remodeled, as PSD scaffolding proteins did not change their amount and localization until a late protein synthesis-dependent third phase. Our findings show how and when spine substructures are remodeled during LTP and explain why synaptic plasticity rules change over time., RIKEN Brain Science Institute, National Institutes of Health (U.S.) (Grant R01DA17310), Human Frontier Science Program (Strasbourg, France), Paul and Anne Punzak Marcus Fund

Objective Inflammatory processes, which provoke alternations of neurotransmitter metabolism, neuroendocrine function, and neuroplasticity in the brain, might promote depression. In depression patients who do not exhibit risk factors, including hypertension, diabetes, coronary heart disease, stroke, Parkinson's disease and dementia, particularly in young people, inflammation is a likely risk factor for depression. We explored whether chronic osteomyelitis (COM), a chronic inflammatory disease, increases depression risk. Methods A Taiwanese national insurance claims data set of more than 22 million enrollees was used to select 15,529 COM patients without depression history and 62,116 randomly selected age- and gender-matched controls without depression and COM history to trace depression development for an 12-year follow-up period from January 1, 1999 to December 31, 2010. The depression risk was analyzed using the Cox proportional hazards regression model. Results The above-mentioned risk factors for depression were more frequent in the COM cohort, who exhibited significantly higher depression risk than the control group did. Comparing only those without comorbidities, the COM group exhibited higher depression risk than the control group did (hazard ratio [HR] = 3.04, 95% confidence interval [CI]: 2.55–3.62). The younger population carried even greater risk (age 65: HR = 1.75, 95% CI: 1.39–2.19). Conclusions This is the first study connecting COM to increased risk of developing depression. The outcomes suggest that COM is a substantial depression predictor and call for a closer focus on these patients for more rigorous depression prevention, particularly in young people.

Anatomical evidence indicates that medial prefrontal cortex (mPFC) neurons project to the dorsal raphe nucleus (DR). In this study, we functionally characterized this descending pathway in rat brain. Projection neurons in the mPFC were identified by antidromic stimulation from the DR. Electrical stimulation of the mPFC mainly inhibited the activity of DR 5-HT neurons (55 of 66). Peristimulus time histograms showed a silence of 150 ± 9 msec poststimulus (latency, 36 ± 1 msec). The administration of WAY-100635 and picrotoxinin partly reversed this inhibition, indicating the involvement of 5-HT1Aand GABAAreceptors. In rats depleted of 5-HT withp-chlorophenylalanine, the electrical stimulation of mPFC mainly activated 5-HT neurons (31 of 40). The excitations (latency, 17 ± 1 msec) were antagonized by MK-801 and NBQX. Likewise, MK-801 prevented the rise in DR 5-HT release induced by electrical stimulation of mPFC. The application of 8-OH-DPAT in mPFC significantly inhibited the firing rate of DR 5-HT neurons and, in dual-probe microdialysis experiments, reduced the 5-HT output in mPFC and DR. Furthermore, the application of WAY-100635 in mPFC significantly antagonized the reduction of 5-HT release produced by systemic 8-OH-DPAT administration in both areas. These results indicate the existence of a complex regulation of DR 5-HT neurons by mPFC afferents. The stimulus-induced excitation of some 5-HT neurons by descending excitatory fibers releases 5-HT, which inhibits the same or other DR neurons by acting on 5-HT1Aautoreceptors. Afferents from the mPFC also inhibit 5-HT neurons through the activation of GABAergic interneurons. Ascending serotonergic pathways may control the activity of this descending pathway by acting on postsynaptic 5-HT1Areceptors.