Glutamate Receptor Antibodies Research Articles

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment-resistant schizophrenia

BackgroundGlutamatergic function abnormalities have been implicated in the etiology of treatment-resistant schizophrenia (TRS), and the efficacy of clozapine may be attributed to its impact on the glutamate system. Recently, evidence has emerged suggesting the involvement of immune processes and increased prevalence of antineuronal antibodies in TRS. This current study aimed to investigate the levels of multiple anti-glutamate receptor antibodies in TRS and explore the effects of clozapine on these antibody levels.MethodsEnzyme linked immunosorbent assay (ELISA) was used to measure and compare the levels of anti-glutamate receptor antibodies (NMDAR, AMPAR, mGlur3, mGluR5) in clozapine-treated TRS patients (TRS-C, n = 37), clozapine-naïve TRS patients (TRS-NC, n = 39), and non-TRS patients (nTRS, n = 35). Clinical symptom severity was assessed using the Positive and Negative Symptom Scale (PANSS), while cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB).ResultThe levels of all four glutamate receptor antibodies in TRS-NC were significantly higher than those in nTRS (p < 0.001) and in TRS-C (p < 0.001), and the antibody levels in TRS-C were comparable to those in nTRS. However, no significant associations were observed between antibody levels and symptom severity or cognitive function across all three groups after FDR correction.ConclusionOur findings suggest that TRS may related to increased anti-glutamate receptor antibody levels and provide further evidence that glutamatergic dysfunction and immune processes may contribute to the pathogenesis of TRS. The impact of clozapine on anti-glutamate receptor antibody levels may be a pharmacological mechanism underlying its therapeutic effects.

Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

Background. The role of recently discovered neurospecific peptides in the pathogenesis of acute and progressive neurologic disorders, their neuroprotective features, and possibilities to use them as markers for the course and prognosis of certain diseases have been actively studied in recent decades. However, neurospecific peptides are almost not studied in chronic residual diseases. In our study we measured the levels of neurospecific peptides and some other markers to achieve understanding of general neurophysiological trends in congenital and acquired chronic non-progressive brain pathology with reference to the selection of relevant groups — study objects. Objective. The aim of the study is to study patterns of neurospecific peptides, neurotransmitters and neuroreceptor markers distribution in the serum of children with various pathogenetic variants of chronic neuropathology. Methods. The study included children from 3 to 16 years old with different pathologies. The sample was divided into groups by pathology type: no sensory and neurological disorders, congenital sensory deficit due to mutation of genes expressed and not expressed in the brain, early acquired sensory deficit of multifactorial nature, congenital mild and severe organic disorders of central nervous system (CNS) in residual stage without baseline sensory deficit, acquired functional CNS disorders without baseline organic defect and sensory deficit. The following laboratory data (neurophysiological components) was studied: nerve growth factor, brain-derived neurotropic factor, neurotrophin-3, neurotrophin-4, neuregulin-1-beta-1, beta-secretase, sirtuin-1, synaptophysin, neuronal nitric oxide synthase, and anti-NR2 glutamate receptor antibodies. The parameters of cognitive activity, sense of vision, sense of smell, and acoustic sense were also evaluated. Results. The study included 274 participants. Neuropeptides and markers have shown a variable degree and range in the group spectrum of differences from normal levels. The most variable in the examined sample was NO-synthase, as well as levels of both neurotrophins, beta-secretase, and glutamate receptor marker. All visual deficits were associated with increased NO-synthase levels (p &lt; 0.001). Neuroplasticity peptides (beta-secretase, neurotrophin-3 and 4) have been activated in all pathological conditions. Nerve growth factor and brain-derived neurotropic factor were specifically activated in mild organic CNS lesions (mild cognitive impairments), while neuregulin — in congenital genetically determined visual deficits. There was no specific activation of neuropeptides and NO-synthase level tended to decrease in cases of severe CNS lesions. Conclusion. The study results suggest that all types of early visual impairment are associated with increased physiological neuronal activity, and non-organic neurological functional disorders — mainly with increased physiological synaptic activity. General neuroplasticity processes were activated in all cases of visual deficits but more specific. However, more specific and well-studied processes were activated in mild organic CNS lesions, and neuroplasticity processes did not activate adequately in severe organic CNS lesions probably due to the limited neuronal and synaptic resources.

Understanding Protein Protocadherin-19 (PCDH19) Syndrome: A Literature Review of the Pathophysiology.

PCDH19 syndrome is a monogenic epilepsy related to the protein protocadherin-19 (PCDH19) gene, which encodes for a protein important for brain development. The protein also seems to regulate gamma-aminobutyric acid type A receptors (GABA(A)(R)). The disease presents with refractory epilepsy that is characterized by seizures occurring in clusters. Till now, the pathophysiology of the disease is mainly unknown, so we conducted a literature review to elucidate the pathophysiology of PCDH19-related epilepsy. We used two databases to investigate this literature review (Google Scholar and PubMed). We selected full-text papers that are published in the English language and published after the year 2000. We selected initially 64 papers and ended up with 29 to conduct this literature review. We found four main theories for the pathophysiology of PCDH19-related epilepsy: GABA(A)(R) dysregulation, blood-brain barrier (BBB) dysfunction, cellular interference, and the AKR1C1-3 gene product deficiency.GABA(A)(R) dysfunction and expression cause decreased effective inhibitory currents predisposing patients to epilepsy. BBB dysfunction allows the passage of methyl-D-aspartate (NMDA)-type glutamate receptor antibodies (abs-NR) through the BBB susceptible membrane. The cellular interference hypothesis establishes that the mutant and non-mutant cells interfere with each other’s communication within the same tissue. Women are more susceptible to being affected by this hypothesis as men only have one copy of the x gene and interference is mediated by this gene, meaning that it cannot occur in them. Finally, downregulation and deficiency of the AKR1C3/AKR1C2 products lead to decreasing levels of allopregnanolone, which diminish the regulation of GABA(A)(R).

Ganglion cell maturation in peripheral neuroblastic tumours of children.

Peripheral neuroblastic tumours of neural crest origin are the most frequent solid neoplasms outside the CNS in children. Neuroblastoma/ganglioneuroblastoma/ganglioneuroma have a natural evolution of histological differentiation over time. Together with mitosis-karyorrhexis index and patient age (International Neuroblastoma Pathology Classification criteria), ganglion cell maturation determines grading and prognosis. Maturation presently is usually assessed only histologically. Immunocytochemical tissue markers defining neuroblast maturation in fetal CNS were here applied to peripheral neuroblastic tumours arising in the adrenal medulla or sympathetic chain. Paraffin sections of resected tumours of 4 toddlers were examined using antibodies demonstrating neuronal identity and maturation: MAP2; synaptophysin; chromogranin-A; NeuN; keratan sulfate (KS); glutamate receptor antibody (GluR2). Synaptophysin, normally a late marker of neuroblast differentiation, was the earliest expressed in neuroblastoma. Others include: Ki67; S-100β protein; vimentin; nestin; α-B-crystallin; neuroblastoma marker PHOX2B. Various degrees of ganglion cell maturation were demonstrated by MAP2, chromogranin, synaptophysin, KS, and GluR2; NeuN was uniformly negative, consistent with sympathetic neurons. KS was sparsely distributed within the tumours in interstitial tissue, within processes of some non-neuronal cells, and adherent to somata and proximal neuritic trunks. Neoplastic ganglion cells with multiple nuclei matured similar to mono-nuclear forms. PHOX2B did not distinguish maturational stages. S-100β protein and α-B-crystallin labeled Schwann cells, especially Schwannian ganglioneuroma. Immunocytochemical markers of neuroblast maturation in fetal brain also are useful in peripheral neuroblastic tumours, providing greater precision than histology alone. The most practical are MAP2, chromogranin-A, and synaptophysin. Prognosis and choice of treatment including chemotherapy might be influenced.

Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights.

Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) ‘Perspective’ article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activity in vitro and in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3 B peptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have ‘frenetic character’- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different ‘faces’ in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.

Infantile neuroaxonal dystrophy with increased titers of glutamate receptor antibodies : a case report

Infantile neuroaxonal dystrophy with increased titers of glutamate receptor antibodies : a case report

Anti-NR2 glutamate receptor antibodies as an early biomarker of cerebral small vessel disease

ObjectivesCerebral small vessel disease (SVD) associated with age and vascular risk factors is one of the leading causes of cognitive disorders as well as ischemic and hemorrhagic strokes. The pathogenesis of this disease has not been fully understood yet. The previously established association of the antibodies against the NR2 subunit of the NMDA receptor (NR2ab) with the mechanisms of SVD such as ischemia and blood–brain barrier (BBB) disruption, might suggest their importance in the brain damage. Design & methodsWe studied the NR2ab serum level in 70 patients (45 females, 61.1 ± 6.3 y.o.) with different severity of cognitive impairment and MRI features of SVD and 20 healthy volunteers (12 females, 58.5 ± 6.4 y.o.). ResultsThe elevated level of NR2ab was associated with subjective cognitive impairment (SCI) (p = 0.028) and mild cognitive impairment (MCI) (p = 0.017), Fazekas grade (F) 2 (p = 0,002) and F3 (p = 0,009) of white matter hyperintensities (WMH) and the numbers of lacunes in the cerebral white matter (less than 5) (p = 0,039). ConclusionThe detected increase in serum NR2ab level in patients with SCI, as well as the minimal amount of white matter lacunes, is most likely caused by hypoxia-induced endothelial damage in the early stage of SVD. Normal NR2ab values in patients with F1 WMH, the increased NR2ab level in patients with F2 and F3 WMH and those with the minimal number of lacunes can indicate that NR2bs are involved in diffuse brain damage due to hypoxia-induced loss of BBB integrity.

Coupled sensory interneurons mediate escape neural circuit processing in an aquatic annelid worm, Lumbriculus variegatus.

The interneurons associated with rapid escape circuits are adapted for fast pathway activation and rapid conduction. An essential aspect of fast activation is the processing of sensory information with limited delays. Although aquatic annelid worms have some of the fastest escape responses in nature, the sensory networks that mediate their escape behavior are not well defined. Here, we demonstrate that the escape circuit of the mud worm, Lumbriculus variegatus, is a segmentally arranged network of sensory interneurons electrically coupled to the central medial giant fiber (MGF), the command-like interneuron for head withdrawal. Electrical stimulation of the body wall evoked fast, short-duration spikelets in the MGF, which we suggest are the product of intermediate giant fiber activation coupled to MGF collateral dendrites. Since these contact sites have immunoreactivity with a glutamate receptor antibody, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dion abolishes evoked MGF responses, we conclude that the afferent pathway for MGF-mediated escape is glutamatergic. This electrically coupled sensory network may facilitate rapid escape activation by enhancing the amplitude of giant axon depolarization.

Nonparaneoplastic autoimmune cerebellar ataxias.

The current review develops the clinical presentations of nonparaneoplastic autoimmune cerebellar ataxia (ACA) and analyzes the association with autoantibodies. Emerging evidence suggests that autoimmunity is involved in a significant proportion of sporadic ataxia cases. Moreover, numerous autoantibodies have recently been described in association with sporadic cerebellar ataxia, improving diagnosis and patient categorization. Nonparaneoplastic ACA encompasses postinfectious acute cerebellar ataxia, opsoclonus-myoclonus-ataxia syndrome, and pure cerebellar ataxia with or without autoantibodies. There is still confusion about how to diagnose and classify the patients, and retrospective data suggest that these very rare entities are in fact largely underrecognized. Numerous autoantibodies have been found associated with sporadic ataxia, improving diagnosis accuracy, and patient categorization. However, although anti-glutamate decarboxylase isotype 65 (GAD65), anti-contactin-associated protein 2 (CASPR2), and anti metabotropic glutamate receptor (mGluR1) antibodies are well recognized biomarkers, many other autoantibodies have been described in very small numbers of patients and their specificity is unknown. Efficient biomarkers for ACA are still lacking and in many cases the diagnosis has to rely on a body of converging evidence.

Clinical Characterization of mGluR5-Antibody Associated Encephalitis

Glutamate receptor antibodies have been implicated in NMDAR encephalitis, AMPAR encephalitis, and mGluR1 cerebellar dysfunction. Now, investigators

Dysfunction of the blood-cerebrospinal fluid-barrier and N-methyl-D-aspartate glutamate receptor antibodies in dementias.

N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.

MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy.

Objective:To describe the features of adult patients with benign, unilateral cerebral cortical encephalitis positive for the myelin oligodendrocyte glycoprotein (MOG) antibody.Methods:In this retrospective, cross-sectional study, after we encountered an index case of MOG antibody–positive unilateral cortical encephalitis with epileptic seizure, we tested for MOG antibody using our in-house, cell-based assay in a cohort of 24 consecutive adult patients with steroid-responsive encephalitis of unknown etiology seen at Tohoku University Hospital (2008–2014). We then analyzed the findings in MOG antibody–positive cases.Results:Three more patients, as well as the index case, were MOG antibody–positive, and all were adult men (median age 37 years, range 23–39 years). The main symptom was generalized epileptic seizure with or without abnormal behavior or consciousness disturbance. Two patients also developed unilateral benign optic neuritis (before or after seizure). In all patients, brain MRI demonstrated unilateral cerebral cortical fluid-attenuated inversion recovery hyperintense lesions, which were swollen and corresponded to hyperperfusion on SPECT. CSF studies showed moderate mononuclear pleocytosis with some polymorphonuclear cells and mildly elevated total protein levels, but myelin basic protein was not elevated. A screening of encephalitis-associated autoantibodies, including aquaporin-4, glutamate receptor, and voltage-gated potassium channel antibodies, was negative. All patients received antiepilepsy drugs and fully recovered after high-dose methylprednisolone, and the unilateral cortical MRI lesions subsequently disappeared. No patient experienced relapse.Conclusions:These MOG antibody–positive cases represent unique benign unilateral cortical encephalitis with epileptic seizure. The pathology may be autoimmune, although the findings differ from MOG antibody–associated demyelination and Rasmussen and other known immune-mediated encephalitides.

Evaluation of titers of antibodies against peptides of subunits NR1 and NR2B of glutamate receptor by enzyme-linked immunosorbent assay in psychiatric patients with anti-thyroid antibodies

BackgroundPatients with anti-thyroid antibodies (ATAs) are reported to exhibit atypical psychiatric symptoms. We have been reported that psychiatric patients with ATAs (PPATs) have anti-N-methyl-Daspartate (NMDA) type glutamate receptor (NMDA-R) antibodies by western blot analysis. NMDA-R forms a tetramer with the subunit glutamate receptors (GluR) GluRζ1 (NR1) and GluRε2 (NR2B). However, the possible etiological role of anti-NR1 and anti-NR2B antibodies in PPATs remains unclear. MethodsFirst, we evaluated titers of anti-NR1 and anti-NR2B antibodies in PPATs by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the relationships among titers of anti-NR1 and anti-NR2B antibodies. Finally, we investigated the relationship between anti-NMDAR antibodies and the psychiatric symptoms in the PPATs. ResultsThere was a strong correlation between anti-NR1 antibodies and anti-NR2B antibodies in the CSF, and some correlation between these antibodies in the serum. High titers of anti-NR2B antibodies in the serum of PPATs contributed to development of hallucinations and high titers of anti-NR1 antibodies in the serum contributed to development of anxiety by logistic regression. ConclusionHigh titers of anti-NR2B antibodies in the serum is a risk factor for hallucinations and high titers of anti-NR1 antibodies in the serum is a risk factor for anxiety in PPATs.

Chapter 12 - Anti-NMDAR encephalitis and other glutamate and GABA receptor antibody encephalopathies

Over the last few year, antibodies to various central nervous system receptors, particularly the glutamate and γ-aminobutyric acid (GABA) receptors, have been found to be associated with autoimmune neurologic disorders. The receptors include the N-methyl-d-aspartate receptor (NMDAR), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), the metabotropic glutamate receptors (mGluRs), and GABA type A and B receptors (respectively GABAAR and GABABR). Compared to the previously described paraneoplastic antibodies directed at intracellular targets, the patients with receptor antibodies are often younger, they less frequently have malignancies, and they respond better to immunotherapy. Many of the patients have limbic encephalitis with amnesia, disorientation, seizures, and psychological or psychiatric symptoms, but those with NMDAR antibodies usually develop a more widespread form of encephalitis, often leading to a decrease in consciousness and requirement for long-term intensive care treatment. The autoantibodies bind directly to the synaptic or extrasynaptic receptors on the membrane surface, and have direct effects on signal transduction in central synapses. These conditions are very important to recognize as the symptoms and complications can be fatal when not treated in time, whereas with immunotherapy many patients recover considerably.

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

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

N-methyl-d-aspartate glutamate receptor (NMDA-R) antibodies in mild cognitive impairment and dementias

The N-methyl-d-aspartate glutamate receptor (NMDA-R) plays a central role in learning and memory and has therefore a potential role in the pathophysiology of neuropsychiatric disorders. Recently, we detected NMDA-R autoantibodies in aged healthy volunteers without neuropsychiatric disorders.Since studies showing the involvement of NMDA-R antibodies in mild cognitive impairment and different forms of dementia are rare, we examined NMDA-R antibodies (Abs) in serum of 46 patients with Alzheimer's disease (AD), 26 patients with subcortical ischemic vascular dementia (SIVD), 18 patients with frontotemporal dementia (FTD), 11 patients with Lewy body disease (LBD) and 33 patients with mild cognitive impairment (MCI) and in 21 healthy aged, gender-matched volunteers. While IgM and/or IgA NMDA-R Abs were present in all groups, IgG was only detected in one AD sample. Seropositivity could be correlated with the presence of co-symptoms: MCI and AD patients suffering from depression and AD and SIVD patients with a psychosis were almost all NMDA-R Ab positive.We conclude that the presence of NMDA-R Abs in dementia could influence the incidence of comorbid depressive and/or psychotic states.

FRI0397 Relationship between Igg Anti-Nr2 Glutamate Receptor Antibodies and Depressive/Anxiety Symptoms in Patients with Systemic Lupus Erythematosus

ObjectivesTo study the relationship between anti-NR2 glutamate receptor antibodies (anti-NR2) and depressive/anxiety symptoms in patients with systemic lupus erythematosus (SLE).MethodsConsecutive Chinese patients who fulfilled ≥4 ACR criteria for SLE were...

Glutamate receptor antibodies directed against AMPA receptors subunit 3 peptide B (GluR3B) can be produced in DBA/2J mice, lower seizure threshold and induce abnormal behavior

Anti-GluR3B antibodies (GluR3B Ab's), directed against peptide B/aa372-395 of GluR3 subunit of glutamate/AMPA receptors, are found in ∼35% of epilepsy patients, activate glutamate/AMPA receptors, evoke ion currents, kill neurons and damage the brain. We recently found that GluR3B Ab's also associate with neurological/psychiatric/behavioral abnormalities in epilepsy patients. Here we asked if GluR3B Ab's could be produced in DBA/2J mice, and also modulate seizure threshold and/or cause behavioral/motor impairments in these mice. DBA/2J mice were immunized with the GluR3B peptide in Complete Freund's Adjuvant (CFA), or with controls: ovalbumin (OVA), CFA, or phosphate-buffer saline (PBS). GluR3B Ab's and OVA Ab's were tested. Seizures were induced in all mice by the chemoconvulsant pentylenetetrazole (PTZ) at three time points, each time with less PTZ to avoid non-specific death. Behavior was examined in Open-Field, RotaRod and Grip tests. GluR3B Ab's were produced only in GluR3B-immunized mice, while OVA Ab's were produced only in OVA-immunized mice, showing high Ab's specificity. In GluR3B Ab's negative mice, seizure severity scores and percentages of animals developing generalized seizures declined in response to decreasing PTZ doses. In contrast, both parameters remained unchanged/high in the GluR3B Ab's positive mice, showing that these mice were more susceptible to seizures. The seizure scores associated significantly with the GluR3B Ab's levels. GluR3B Ab's positive mice were also more anxious in Open-Field test, fell faster in RotaRod test, and fell more in Grip test, compared to all the control mice. GluR3B Ab's are produced in DBA/2J mice, facilitate seizures and induce behavioral/motor impairments. This animal model can therefore serve for studying autoimmune epilepsy and abnormal behavior mediated by pathogenic anti-GluR3B Ab's.

Glutamate receptor antibodies directed against AMPA receptors subunit 3 peptide B (GluR3B) associate with some cognitive/psychiatric/behavioral abnormalities in epilepsy patients

Antibodies (Ab's) to glutamate receptors, directed specifically against AMPA receptors subunit 3 peptide B (i.e. GluR3 amino acids 372-395), named GluR3B Ab's, can by themselves activate GluR3-containing glutamate/AMPA receptors, evoke ion currents via the receptor's ion channel, kill neurons and damage the brain. Herein we first tested 14 consecutive epilepsy patients and 10 healthy controls, and found that 7 (50%) patients had GluR3B Ab's. Second, in 71 other consecutive epilepsy patients (20 generalized epilepsy, 51 partial epilepsy) and 49 controls, we found that 17 (24%) patients had GluR3B Ab's, of which 8 had generalized and 9 partial epilepsy. We then studied 41 epilepsy patients: 21 patients with GluR3B Ab's and 20 without such Ab's (pooled of both tests without biased selection), for possible association of GluR3B Ab's with disease severity and/or neurobehavioral/cognitive comorbidities. Of the 21 patients with GluR3B Ab's, 6 had symptomatic, 7 cryptogenic, and 8 idiopathic epilepsy. Of the 20 patients without GluR3B Ab's, 16 had idiopathic etiology, and 4 nonidiopathic epilepsy. We found that among the 21 patients with GluR3B Ab's, 19 patients (90%) had learning problems, 16 (76%) attention problems, and 15 (71%) psychiatric problems. In contrast, among the 20 patients without GluR3B Ab's, only 6 (30%) had learning problems (p<0.0001), 5 (25%) attention problems (p=0.0017), and 2 (10%) psychiatric problems (p<0.0001). These findings suggest either that neurobehavioral abnormalities occur more frequently in epilepsy patients already having GluR3B Ab's, and may be due to them, or that GluR3B Ab's are more frequent in patients already having neurobehavioral abnormalities.

OP0061 Seizures in systemic lupus erythematosus: A prospective study of predictors and outcomes in a large, international, disease inception cohort

BackgroundSeizures are a manifestation of neuropsychiatric (NP) SLE and occur in 6% to 51% of adult and pediatric patients.ObjectivesTo describe the frequency, attribution and outcome of seizure disorders and to...