Ketamine nasal spray rapidly relieves depression and suicidal thoughts, finds trial | The Independent

People with serious mental illness could one day be offered a nasal
spray of ketamine after a clinical trial showed the drug can rapidly
tackle bouts of severe depression and suicidal thoughts.
In just a matter of hours, doctors, and the patients themselves,
measured a significant improvement in symptoms of patients classed as
being at high risk of suicide.
The trial of antidepressant esketamine by Yale University researchers
and the manufacturer, Janssen, suggests it could be effective in
bridging the gap where conventional antidepressants take weeks to
be fully effective.

Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii

 "Toxoplasma gondii is a pathogen implicated in psychiatric disorders. As elevated antibodies to T. gondii are also present in non-symptomatic individuals, we hypothesized that the age during first exposure to the pathogen may affect symptom manifestation. We tested this hypothesis by evaluating neurobehavioral abnormalities and the immune response in mice following adolescent or adult T. gondii infection.

Methods

Mice were infected with T. gondii at postnatal day 33 (adolescent/juvenile) or 61 (adult). At 8 weeks post-infection (wpi), pre-pulse inhibition of the acoustic startle (PPI) in mice administered MK-801 (0.1 and 0.3 mg/kg) and amphetamine (5 and 10 mg/kg) was assessed. Peripheral (anti-T. gondii, C1q-associated IgG and anti-GLUN2 antibodies) and central (C1q and Iba1) markers of the immune response were also evaluated. In addition, regional brain expression of N-methyl-d-aspartate receptor (NMDAR) subunits (GLUN1 and GLUN2A), glutamatergic (vGLUT1, PSD95) and GABAergic (GAD67) markers, and monoamines (DA, NE, 5-HT) and their metabolites were measured.

Results

Juvenile and adult infected mice exhibited opposite effects of MK-801 on PPI, with decreased PPI in juveniles and increased PPI in adults. There was a significantly greater elevation of GLUN2 autoantibodies in juvenile-compared to adult-infected mice. In addition, age-dependent differences were found in regional expression of NMDAR subunits and markers of glutamatergic, GABAergic, and monoaminergic systems. Activated microglia and C1q elevations were found in both juvenile- and adult-T. gondii infected mice.

Conclusions

Our study demonstrates that the age at first exposure to T. gondii is an important factor in shaping distinct behavioral and neurobiological abnormalities. Elevation in GLUN2 autoantibodies or complement protein C1q may be a potential underlying mechanism. A better understanding of these age-related differences may lead to more efficient treatments of behavioral disorders associated with T. gondii infection."



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Animal models reveal promising approach to slow brain degeneration in Huntington's disease - Medical News Today

Research presented by Dr. Lynn Raymond, from the University of British
Columbia, shows that blocking a specific class of glutamate receptors,
called extrasynaptic NMDA receptors, (with memantine )can improve motor learning and
coordination, and prevent cell death in animal models of Huntington
disease. As Huntington disease is an inherited condition that can be
detected decades before any clinical symptoms are seen in humans, a
better understanding of the earliest changes in brain cell (neuronal)
function, and the molecular pathways underlying those changes, could
lead to preventive treatments that delay the onset of symptoms and
neurodegeneration.

A fast-acting antidepressant appears within reach (NMDA antagonist and monoamine uptake blocker))

A new study suggests a fast-acting antidepressant may be on the horizon. In mice, the drug produces evidence of a mood lift within 24 hours and then continues working for sustained relief.

The drug, referred to by Talbot as its coded name MI-4 and better known among scientists as Ro-25-6981 ( a selective NMDA 2B receptor subtype antagonist (GRIN2B), has been shown by previous researchers to cause a rapid antidepressant effect in animals by blocking one of the brain's signaling chemicals. But until now, researchers were not aware of the full spectrum of its antidepressant properties.
The new study bolsters the evidence for MI-4's rapid effect and adds
an exciting twist: MI-4 also works in the long term. Moreover, it may
accomplish its long-term effects through a three-pronged approach known
as triple reuptake inhibition, which refers to a drug's ability to
simultaneously increase the levels of three key chemicals in the brain
that are known to affect mood and feelings of pleasure—dopamine,
norepinephrine and serotonin. Most depression drugs only target one of
these chemicals, which may explain why they are not effective in all
patients.

Related articles

• Novel Antidepressant in the Pipeline: NMDA Receptor Antagonists (medicineandtechnology.com)

Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis.

Objective: To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: Clinical and radiological analysis of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent MRI and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of NMO-spectrum disorder (5 cases, 4 anti-AQP4-positive), or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG-positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4-positive, 2 MOG-positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis: NMDAR-antibodies were detected only in the 50 anti-NMDAR patients, MOG-antibodies in 3/50 anti-NMDAR and 1/56 NMO patients, and AQP4-antibodies in 48/56 NMO and 1/50 anti-NMDAR patients (p

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca2+ mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.

PLOS Biology: Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes

Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report.

Relapsing symptoms post herpes simplex virus 1 (HSV) encephalitis (HSVE) usually occur a few weeks after viral therapy and represent either 1) a true viral relapse of HSVE (CSF PCR positive for HSV, new necrotic lesions on brain MRI, and response to acyclovir therapy) or 2) a disorder postulated to be immune-mediated (CSF negative for HSV, no new necrotic lesions, and no response to acyclovir).(1,2) It has been suggested that this immune-mediated disorder may be related to NMDA receptor (NMDAR) antibodies,(3) and we recently reported a child in whom relapsing symptoms post HSVE were the presentation of anti-NMDAR encephalitis.(4) We report an adult with this disorder, demonstrate that synthesis of NMDAR antibodies began after HSVE, and show that relapsing symptoms were due to steroid-responsive anti-NMDAR encephalitis.

Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor.

BACKGROUND:

Movement disorder relapses after herpes simplex virus 1 (HSV1) encephalitis have been hypothesized to be secondary to postviral autoimmunity. Recently, a proportion of patients with HSV1 encephalitis (HSE) were shown to produce autoantibodies against N-methyl-D-aspartate receptor (NMDAR).

METHODS:

We measured autoantibodies against NMDAR and dopamine-2 receptor (D2R) expressed at the cell surface in the stored acute serum of 9 children with HSE, 3 of whom had a relapsing course with chorea.

RESULTS:

The 3 patients with chorea had elevated autoantibodies against NMDAR (n = 1), D2R (n = 1), or both (n = 1), whereas patients without chorea were negative (n = 6). The prospectively identified patient with chorea and NMDAR autoantibodies improved after early treatment with steroids, intravenous immunoglobulin, and cyclophosphamide, with reduction in serum NMDAR antibody titers.

CONCLUSIONS:

These autoantibody findings lend support to the autoimmune hypothesis and the early use of immune suppression in post-HSE chorea.

Neuropsychopharmacology - Abstract of article: Abnormalities in White Matter Microstructure Associated with Chronic Ketamine Use

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast-acting antidepressant. It is also a relatively widespread drug of abuse, particularly in China and the UK. Acute administration has been well characterized, but the effect of extended periods of ketamine use—on brain structure in humans—remains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug-using controls, and we used probabilistic tractography to quantify changes in corticosubcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared with controls. Within the ketamine-user group, we found a significant positive association between the connectivity profile between the caudate nucleus and the lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use.

Molecular Psychiatry - Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity

In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood–brain barrier (ApoE−/−) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE−/− mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood–brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E−08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood–brain barrier function.

The Major Brain Cholesterol Metabolite 24(S)-Hydroxycholesterol Is a Potent Allosteric Modulator of N-Methyl-d-Aspartate Receptors

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulate NMDARs experimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Here we show that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator of NMDARs with a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABA_A receptors (GABA_ARs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulate NMDARs at concentrations ≤10 μM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated with NMDAR channel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development.

The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia.

Kynurenic acid is a tryptophan metabolite that is synthesized and released in the brain by astrocytes and acts as an antagonist of nicotinic acetylcholine receptors and N-methyl-d-aspartate glutamate receptors, both of which are critically involved in cognition as well as neural plasticity and brain development. The concentration of kynurenic acid is increased in the brains of persons with schizophrenia and this increase has been implicated in the cognitive and social impairments associatedwith the disease. In addition, growing evidence suggests that the increase in kynurenic acid may begin early in life. For example, exposure to influenza A virus during development results in a transient increase in kynurenic acid concentration that could disrupt normal brain development and lead to cognitive deficits later in life. Changes in kynurenic acid may thus provide a link between developmental exposure to viruses and the increased risk of subsequently developing schizophrenia. To test this, we mimicked the effects of influenza A exposure by treating rats with kynurenine, the precursor of kynurenic acid, on postnatal days 7-10. We observed a transient increase in both kynurenic acid and quinolinic acid during treatment. When rats were subsequently behaviorally tested as adults, those previously treated with kynurenine exhibited decreased social behavior and locomotor activity. In contrast, attentional function and fear conditioning were not affected. Together with other recent findings, these data have several implications for understanding how viral-induced changes in tryptophan metabolism during development may contribute to schizophrenia-related symptoms later in life.

Neuropsychopharmacology - Abstract of article: NMDA Receptor Blockade by Ketamine Abrogates Lipopolysaccharide-Induced Depressive-Like Behavior in C57BL/6J Mice

We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O’Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokine expression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA receptor glutamatergic neurotransmission after NMDA receptor antagonism by ketamine. NBQX administered at the dose of 10 mg/kg intraperitoneally 15 min before ketamine in mice treated with LPS 24 h earlier restored LPS-induced decreased sucrose preference. These findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

Opposite Roles of NMDA Receptors in Relapsing and Primary Progressive Multiple Sclerosis.

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.

ACTH protects mature oligodendroglia from excitotoxic and inflammation-related damage in vitro.

Corticosteroids (CS) are widely employed to treat relapses in multiple sclerosis (MS). Endogenous ACTH is a 39-amino acid peptide that, among other functions, stimulates CS production. Exogenous ACTH 1-39 is used to treat MS relapses, presumably by stimulating endogenous CS production. However, unlike CS, ACTH binds to melanocortin receptors, found in the central nervous system (CNS) as well as on inflammatory cells. Since glia are implicated in MS and other neurodegenerative diseases, and oligodendroglia (OL) are more sensitive to injury than other glia, we characterized the protective effects of ACTH on OL in vitro without the confounding effects of CS. Rat brain cultures containing OL, astrocytes (AS), and microglia (MG) were incubated for 1 day with potentially cytotoxic agents with or without preincubation with ACTH 1-39. The cytotoxic agents killed 55-70% of mature OL, but caused little or no death of AS or MG at the concentrations used. ACTH protected OL from death induced by staurosporine, AMPA, NMDA, kainate, quinolinic acid, or reactive oxygen species, but did not protect against kynurenic acid or nitric oxide. The protective effects of ACTH were dose dependent, and decreased OL death induced by the different agents by 30-60% at 200 nM ACTH. We show for the first time that melanocortin 4 receptor is expressed on OL in addition to MG and AS. In summary, ACTH 1-39 protects OL in vitro from several excitotoxic and inflammation-related insults. ACTH may be activating melanocortin receptors on OL or alternately on AS or MG to prevent OL death.

NIMH · Ketamine Cousin GLYX-13 Rapidly Lifts Depression Without Side Effects

Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons.

These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.

Treatment-resistant Depression | Glutamate, Stress Hormones, and their Role in the Regeneration of NeuronsThe New York Academy of Sciences

The standard of care for clinical depression has significant limitations: traditional drugs that focus on monoamine neurotransmitters can take several weeks to be effective, and many patients never respond to any form of treatment. Several clinical trials have demonstrated strikingly better outcomes using the anesthetic ketamine to treat depression. Notably, a single application can have rapid and lasting antidepressant effects in patients who do not respond to other treatments. Because ketamine is an antagonist of NMDA-type glutamate receptors, research is focused on the role of glutamate neurotransmission in depression and on drug development that targets the glutamatergic system. The March 25, 2013, meeting of the Academy's Biochemical Pharmacology Discussion Group, Treatment-resistant Depression: Glutamate, Stress Hormones, and their Role in the Regeneration of Neurons, presented this new research and the avenues it is opening for the treatment of depression.

NMDA Receptor Blockade by Ketamine Abrogates Lipopolysaccharide-Induced Depressive-Like Behavior in C57BL/6J Mice.

We have previously demonstrated that lipopolysaccharide (LPS) induces depressive-like behavior by activating indoleamine 2,3 dioxygenase (IDO; O'Connor et al, 2009c). IDO degrades tryptophan along the kynurenine pathway. Using mass-spectrometry (LC-MS) analysis of kynurenine metabolites in the brain of mice injected at the periphery with 1 mg/kg LPS, we show that LPS activates the kynurenine 3-monooxygenase pathway that ultimately degrades kynurenine into quinolinic acid. As quinolinic acid acts as an N-methyl-D-aspartate (NMDA) receptor agonist, we used the NMDA receptor antagonist ketamine to assess the role of NMDA receptor activation in LPS-induced depressive-like behavior. Here, we report that a low dose of ketamine (6 mg/kg, intraperitoneally) immediately before administration of LPS (0.83 mg/kg, intraperitoneally) in C57Bl/6 J mice abrogated the development of LPS-induced depressive-like behavior, without altering LPS-induced sickness measured by body weight loss, decreased motor activity, and reduced food intake. Depressive-like behavior was measured 24 h after LPS by decreased sucrose preference and increased immobility in the forced swim test (FST). Ketamine had no effect on LPS-induced cytokineexpression in the liver and brain, IDO activation, and brain-derived neurotrophic factor (BDNF) transcripts. The ability of ketamine to abrogate LPS-induced depressive-like behavior independently of a possible interference with LPS-induced inflammatory signaling was confirmed when ketamine was administered 10 h after LPS instead of immediately before LPS. In contrast, ketamine had no effect when administered 24 h before LPS. To confirm that NMDA receptor antagonism by ketamine mediates the antidepressant-like activity of this compound in LPS-treated mice, mice were pretreated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX) to block enhanced AMPA receptor glutamatergic neurotransmission after NMDA receptor antagonism by ketamine. NBQX administered at the dose of 10 mg/kg intraperitoneally 15 min before ketamine in mice treated with LPS 24 h earlier restored LPS-induced decreased sucrose preference. These findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

Molecular Psychiatry - Pathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion

Perturbation of Disrupted-In-Schizophrenia-1 (DISC1) and d-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates d-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in d-serine production. To elucidate DISC1–SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source ofd-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of d-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of d-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in d-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.