Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NMDA receptors are activated after binding of the agonist glutamate to the NR2 subunit along with a co-agonist, either L-glycine or D-serine, to the NR1 subunit. There is substantial evidence to suggest that D-serine is the most relevant co-agonist in forebrain regions and that alterations in D-serine levels contribute to psychiatric disorders. D-serine is produced through isomerization of L-serine by serine racemase (Srr), either in neurons or in astrocytes. It is released by astrocytes by an activity-dependent mechanism involving secretory vesicles. In the present study we generated transgenic mice (SrrTg) expressing serine racemase under a human GFAP promoter. These mice were biochemically and behaviorally analyzed using paradigms of anxiety, depression and cognition. Furthermore, we investigated the behavioral effects of long-term administration of D-serine added to the drinking water. Elevated brain D-serine levels in SrrTg mice resulted in specific behavioral phenotypes in the forced swim, novelty suppression of feeding and olfactory bulbectomy paradigms that are indicative of a reduced proneness towards depression-related behavior. Chronic dietary D-serine supplement mimics the depression-related behavioral phenotype observed in SrrTg mice. Our results suggest that D-serine supplementation may improve mood disorders.
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PMID:Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior. 2380 96

Phosphorylation of N-methyl-D-aspartate (NMDA) receptors is a major regulatory mechanism underlying synaptic plasticity. However, changes in NMDA receptors and phosphorylation after traumatic brain injury (TBI) remain incompletely understood. Using an animal TBI model, we observed that the protein level of NMDA receptor subunit NR2B was downregulated in synaptosomal fractions obtained from the ipsilateral neocortical injury region, whereas the levels of NR2A, NR1, and PSD93 were not significantly altered at 4 and 24 hours after TBI. Further investigation showed that tyrosine phosphorylations of NR2B Y1472 and PSD93 Y340 in synaptosomal fractions were significantly decreased relative to their total protein level after TBI. Correspondingly, phosphorylation of the Src-kinase-inhibitory site Y527 was increased, whereas phosphorylation of the activation site Y416 was decreased, indicating that the activity of Src kinase is significantly inhibited after TBI. In comparison, other Src family kinase substrates of NMDA receptor, NR2A Y1246, NR2A Y1325, and NR2B Y1070 were not obviously affected after TBI. The results suggest that TBI downregulates the Src-kinase-mediated phosphorylation of NR2 and PSD93 to destabilize the synaptic localization of NMDA receptors. Therefore, post-TBI loss of NMDA receptors may contribute to the depression of synaptic activity after TBI.
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PMID:Downregulation of Src-kinase and glutamate-receptor phosphorylation after traumatic brain injury. 2383 28

Adolescence is a time of continued brain maturation, particularly in limbic and cortical regions, which undoubtedly plays a role in the physiological and emotional changes. Juvenile rats repeatedly exposed to prenatal stress (PS) exhibit behavioral features often observed in neuropsychiatric disorders including depression. However, to date the underlying neurological mechanisms are still unclear. In the current study, juvenile offspring rats whose mothers were exposed to PS were evaluated for depression-related behaviors in open field and sucrose preference test. NMDA receptor subunits NR1 and NR2A in the hippocampus, frontal cortex and striatum were assayed by western blotting. The results indicated that PS resulted in several behavioral anomalies in the OFT and sucrose preference test. Moreover, reduced levels of NMDA receptor subunits NR1 and NR2A in the hippocampus, and NR1 in prefrontal cortex and striatum of prenatally stressed juvenile offspring were found. Treatment with MK-801 to pregnant dams could prevent all those changes in the juvenile offspring. Collectivity, these data support the argument that PS to pregnant dams could induce depression-like behavior, which may be involved with abnormal expression of NR1 and NR2A in specific brain regions, and MK-801 may have antidepressant-like effects on the juvenile offspring.
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PMID:Reduced levels of NR1 and NR2A with depression-like behavior in different brain regions in prenatally stressed juvenile offspring. 2427 57

Excitatory responses evoked by N-methyl-d-aspartate (NMDA) in the vestibular nuclei (VN) of the rat were studied in vivo during microiontophoretic application of noradrenaline (NA) and/or its agonists and antagonists. Ejection of NA-modified excitatory responses mediated by NMDA receptors (NMDAR) in all neurons tested; the effect was enhancement in 59% of cases and depression in the remaining 41%. Enhancements prevailed in all VN with the exception of the lateral vestibular nucleus, where both effects were recorded in an equal number of cases. The enhancing action of NA on NMDAR-mediated responses was mimicked by the noradrenergic beta-receptor agonist isoproterenol, the beta1 specific agonist denopamine and the alpha2 agonist clonidine. These effects were blocked respectively by the generic beta-receptor antagonist timolol, the beta1 antagonist atenolol and the alpha2 antagonist yohimbine. In contrast, application of the alpha1 receptor agonist cirazoline and the specific alpha1 antagonist prazosin respectively mimicked and partially antagonized the depression of NMDAR-mediated excitations induced by NA. Double-labeling immunohistochemical techniques demonstrated broad colocalization of NMDAR (specifically NR1 and NR2 subunits) with noradrenergic receptors (alpha1, alpha2 and beta1) in many VN neurons; only minor differences were found between nuclei. These results indicate that NA can produce generalized modulation of NMDAR-mediated excitatory neurotransmission in VN, which may in turn modify synaptic plasticity within the nuclei.
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PMID:Noradrenergic modulation of neuronal responses to n-methyl-d-aspartate in the vestibular nuclei: an electrophysiological and immunohistochemical study. 2450 45

Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, Sarm1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that Sarm1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether Sarm1 knockdown affects the synaptic responses of neurons. We here show that reduced Sarm1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in Sarm1 knockdown mice, suggesting a role for Sarm1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of Sarm1. In conclusion, our study demonstrates a role for Sarm1 in the regulation of synaptic plasticity. Through these mechanisms, Sarm1 knockdown results in the impairment of associative memory and social interactions in mice.
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PMID:Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. 2474 98

Commonly used anesthetic agents, e.g. ketamine, may be neurotoxic to the developing brain but there has been little attention to the neurobehavioral consequences for offspring when used for maternal anesthesia. We hypothesize that treatment of pregnant rats with ketamine during the second trimester would affect brain development of the offspring. Pregnant rats on gestational day 14, about equal to midtrimester pregnancy in humans, received a sedative dose of ketamine intravenously for 2h. Brain hippocampal morphology of their pups at postnatal days 0 (P0) and P30 was examined by Nissl-staining and the characteristics of dendrites were determined using the Golgi-Cox staining, while cell proliferation in subventricular zone (SVZ) and dentate gyrus (DG) was labeled with bromodeoxyuridine (BrdU). Their neurobehavioral functions were tested at P25-30 after which the NR1 and NR2 subunits of N-methyl-d-aspartate (NMDA) receptor, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) in the hippocampus were analyzed by western blot. When pregnant rats were exposed to ketamine, there was neuronal loss, pyramidal neuronal abnormality and reduced cell proliferation in the hippocampus of offspring. These morphological abnormalities were associated with depression- and anxiety-like behaviors, and impaired memory up to young adult age. The treatment further caused NR2A receptor subunit up-regulation and NR2B receptor subunit, BDNF and PSD-95 down-regulation. These data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits.
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PMID:Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring. 2478 Apr 97

Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti-glutamate receptor antibodies is discussed separately in this very comprehensive review, with regards to: the human diseases in which these anti-glutamate receptor antibodies were found thus far, their presence and production in the nervous system, their association with various psychiatric/behavioral/cognitive/motor impairments, their possible association with certain infectious organisms, their detrimental effects in vitro as well as in vivo in animal models in mice, rats or rabbits, and their diverse and unique mechanisms of action. The review also covers the very encouraging positive responses to immunotherapy of some patients that have either of the above-mentioned anti-glutamate receptor antibodies, and that suffer from various neurological diseases/problems. All the above are also summarized in the review's five schematic and useful figures, for each type of anti-glutamate receptor antibodies separately. The review ends with a summary of all the main findings, and with recommended guidelines for diagnosis, therapy, drug design and future investigations. In the nut shell, the human studies, the in vitro studies, as well as the in vivo studies in animal models in mice, rats and rabbit revealed the following findings regarding the five different types of anti-glutamate receptor antibodies: (1) Anti-AMPA-GluR3B antibodies are present in ~25-30% of patients with different types of Epilepsy. When these anti-glutamate receptor antibodies (or other types of autoimmune antibodies) are found in Epilepsy patients, and when these autoimmune antibodies are suspected to induce or aggravate the seizures and/or the cognitive/psychiatric/behavioral impairments that sometimes accompany the seizures, the Epilepsy is called 'Autoimmune Epilepsy'. In some patients with 'Autoimmune Epilepsy' the anti-AMPA-GluR3B antibodies associate significantly with psychiatric/cognitive/behavior abnormalities. In vitro and/or in animal models, the anti-AMPA-GluR3B antibodies by themselves induce many pathological effects: they activate glutamate/AMPA receptors, kill neurons by 'Excitotoxicity', and/or by complement activation modulated by complement regulatory proteins, cause multiple brain damage, aggravate chemoconvulsant-induced seizures, and also induce behavioral/motor impairments. Some patients with 'Autoimmune Epilepsy' that have anti-AMPA-GluR3B antibodies respond well (although sometimes transiently) to immunotherapy, and thanks to that have reduced seizures and overall improved neurological functions. (2) Anti-NMDA-NR1 antibodies are present in patients with autoimmune 'Anti-NMDA-receptor Encephalitis'. In humans, in animal models and in vitro the anti-NMDA-NR1 antibodies can be very pathogenic since they can cause a pronounced decrease of surface NMDA receptors expressed in hippocampal neurons, and also decrease the cluster density and synaptic localization of the NMDA receptors. The anti-NMDA-NR1 antibodies induce these effects by crosslinking and internalization of the NMDA receptors. Such changes can impair glutamate signaling via the NMDA receptors and lead to various neuronal/behavior/cognitive/psychiatric abnormalities. Anti-NMDA-NR1 antibodies are frequently present in high levels in the CSF of the patients with 'Anti-NMDA-receptor encephalitis' due to their intrathecal production. Many patients with 'Anti-NMDA receptor Encephalitis' respond well to several modes of immunotherapy. (3) Anti-NMDA-NR2A/B antibodies are present in a substantial number of patients with Systemic Lupus Erythematosus (SLE) with or without neuropsychiatric problems. The exact percentage of SLE patients having anti-NMDA-NR2A/B antibodies varies in different studies from 14 to 35%, and in one study such antibodies were found in 81% of patients with diffuse 'Neuropshychiatric SLE', and in 44% of patients with focal 'Neuropshychiatric SLE'. Anti-NMDA-NR2A/B antibodies are also present in subpopulations of patients with Epilepsy of several types, Encephalitis of several types (e.g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1 antibodies into the brain of mice, the mice became ataxic. Anti-mGluR1 antibodies derived from patients with Ataxia also caused disturbance of eye movements in animal models. Immunotherapy can be very effective for some Cerebellar Ataxia patients that have anti-mGluR1 antibodies. (5) Anti-mGluR5 antibodies were found thus far in the serum and CSF of very few patients with Hodgkin lymphoma and Limbic Encephalopathy (Ophelia syndrome). The sera of these patients that contained anti-GluR5 antibodies reacted with the neuropil of the hippocampus and cell surface of live rat hippocampal neurons, and immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was indeed mGluR5. Taken together, all these evidences show that anti-glutamate receptor antibodies are much more frequent among various neurological diseases than ever realized before, and that they are very detrimental to the nervous system. As such, they call for diagnosis, therapeutic removal or silencing and future studies. What we have learned by now about the broad family of anti-glutamate receptor antibodies is so exciting, novel, unique and important, that it makes all future efforts worthy and essential.
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PMID:Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. 2508 Oct 16

Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-d-aspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar d-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist, which alone only partially inhibits NMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN-sensitive NMDARs are essential for LTP induction.
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PMID:Sensitivity of N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices. 2541 30

The control of sympathetic outflow in the chronic heart failure (CHF) state is markedly abnormal. Patients with heart failure present with increased plasma norepinephrine and increased sympathetic nerve activity. The mechanism for this sympatho-excitation is multiple and varied. Both depression in negative feedback sensory control mechanisms and augmentation of excitatory reflexes contribute to this sympatho-excitation. These include the arterial baroreflex, cardiac reflexes, arterial chemoreflexes and cardiac sympathetic afferent reflexes. In addition, abnormalities in central signaling in autonomic pathways have been implicated in the sympatho-excitatory process in CHF. These mechanisms include increases in central Angiotensin II and the Type 1 receptor, increased in reactive oxygen stress, upregulation in glutamate signaling and NR1 (N-methyl-D-aspartate subtype 1) receptors and others. Exercise training in the CHF state has been shown to reduce sympathetic outflow and result in increased survival and reduced cardiac events. Exercise training has been shown to reduce central Angiotensin II signaling including the Type 1 receptor and reduce oxidative stress by lowering the expression of many of the subunits of NADPH oxidase. In addition, there are profound effects on the central generation of nitric oxide and nitric oxide synthase in sympatho-regulatory areas of the brain. Recent studies have pointed to the balance between Angiotensin Converting Enzyme (ACE) and ACE2, translating into Angiotensin II and Angiotensin 1-7 as important regulators of sympathetic outflow. These enzymes appear to be normalized following exercise training in CHF. Understanding the precise molecular mechanisms by which exercise training is sympatho-inhibitory will uncover new targets for therapy.
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PMID:Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure. 2545 27

During cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the sub-synaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons - including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development.
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PMID:Presynaptic NMDA receptors - dynamics and distribution in developing axons in vitro and in vivo. 2552 35


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