The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders.

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MTLE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MTLE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n=8) of MTLE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p=0.014), hsa-miR-212-3p: mean decrease of 76.9% (p=0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11, MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export.

The search for circulating epilepsy biomarkers.

Few would experience greater benefit from the development of biomarkers than those who suffer from epilepsy. Both the timing of individual seizures and the overall course of the disease are highly unpredictable, and the associated morbidity is considerable. Thus, there is an urgent need to develop biomarkers that can predict the progression of epilepsy and treatment response. Doing so may also shed light on the mechanisms of epileptogenesis and pharmacoresistance, which remain elusive despite decades of study. However, recent advances suggest the possible identification of circulating epilepsy biomarkers - accessible in blood, cerebrospinal fluid or urine. In this review, we focus on advances in several areas: neuroimmunology and inflammation; neurological viral infection; exemplary pediatric syndromes; and the genetics of pharmacoresistance, as relevant to epilepsy. These are fertile areas of study with great potential to yield accessible epilepsy biomarkers.

Genetics of the epilepsies: where are we and where are we going?

PURPOSE OF REVIEW: We aim to review the most recent advances in the field of epilepsy genetics with particular focus on the progress in gene discovery in monogenic epilepsies, identification of risk genes in complex genetic epilepsies and recent findings in the field of epilepsy pharmacogenomics. RECENT FINDINGS: During the last 12 months, the use of massive parallel sequencing technologies has allowed for the discovery of several genes for monogenic epilepsies. Most importantly, PRRT2 was identified as the long-sought gene for benign familial infantile seizures. Mutations in KCNT1 were found in two seemingly unrelated monogenic epilepsies including malignant migrating partial seizures of infancy and severe autosomal dominant nocturnal frontal lobe epilepsy. A genome-wide association study in idiopathic generalized epilepsy revealed the first common risk variants for human seizure disorders including variants in VRK2, PNPO and SCN1A. Furthermore, a landmark study provided evidence that screening for the HLA-B1502 variant may prevent carbamazepine CBZ-induced side effects in the Taiwanese population. Also, HLA-A3101 variants were identified as a risk factor for carbamazepine side effects in Europeans. SUMMARY: Novel technologies and an unprecedented level of international collaboration have resulted in identification of novel genes for monogenic and complex genetic epilepsies as well as risk factors for side effects of antiepileptic drugs. This review provides an overview of the most relevant studies in the last year and highlights the future direction of the field.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy.

Neurogenesis in the hippocampal dentate gyrus persists throughout life and is increased by seizures. The dentate granule cell (DGC) layer is often abnormal in human and experimental temporal lobe epilepsy, with dispersion of the layer and the appearance of ectopic granule neurons in the hilus. We tested the hypothesis that these abnormalities result from aberrant DGC neurogenesis after seizure-induced injury. Bromodeoxyuridine labeling, in situ hybridization, and immunohistochemistry were used to identify proliferating progenitors and mature DGCs in the adult rat pilocarpine temporal lobe epilepsy model. We also examined dentate gyri from epileptic human hippocampal surgical specimens. Prox-1 immunohistochemistry and pulse-chase bromodeoxyuridine labeling showed that progenitors migrate aberrantly to the hilus and molecular layer after prolonged seizures and differentiate into ectopic DGCs in rat. Neuroblast marker expression indicated the delayed appearance of chainlike progenitor cell formations extending into the hilus and molecular layer, suggesting that seizures alter migratory behavior of DGC precursors. Ectopic putative DGCs also were found in the hilus and molecular layer of epileptic human dentate gyrus. These findings indicate that seizure-induced abnormalities of neuroblast migration lead to abnormal integration of newborn DGCs in the epileptic adult hippocampus, and implicate aberrant neurogenesis in the development or progression of recurrent seizures.

A web-based federated neuroinformatics model for surgical planning and clinical research applications in epilepsy.

There is an increasing need to efficiently share diverse clinical and image data among different clinics, labs, and departments of a medical center enterprise to facilitate better quality care and more effective clinical research. In this paper, we describe a web-based, federated information model as a viable technical solution with applications in medical refractory epilepsy and other neurological disorders. We describe four such online applications developed in a federated system prototype: surgical planning, image analysis, statistical data analysis, and dynamic extraction, transforming, and loading (ETL) of data from a heterogeneous collection of data sources into an epilepsy multimedia data warehouse (EMDW). The federated information system adopts a three-tiered architecture, consisting of a user-interface layer, an application logic layer, and a data service layer. We implemented two complementary federated information technologies, i.e., XML (eXtensible Markup Language) and CORBA (Common Object Request Broker Architecture), in the prototype to enable multimedia data exchange and brain images transmission. The preliminary results show that the federated prototype system provides a uniform interface, heterogeneous information integration and efficient data sharing for users in our institution who are concerned with the care of patients with epilepsy and who pursue research in this area.