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      Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects

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          Abstract

          Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson’s disease. To determine whether drugs that enhance BAP complexity produces positive outcomes, we used light pulses to trigger seizures in a model of Dravet syndrome, an intractable genetic epilepsy. The highest-ranked compounds identified by BAP analysis exhibit far greater anti-seizure efficacy and fewer side effects during subsequent in-depth behavioral assessment. This high correlation with behavioral outcomes illustrates the power of brain activity pattern-based screens and identifies novel therapeutic candidates with minimal side effects.

          Abstract

          One challenge in drug screening for neurological disorders is how to accurately capture disease pathology and side effects. Here, the authors developed a multi-channel recording platform based on a zebrafish genetic model of epilepsy to screen for antiepileptic drugs.

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          A systematic genome-wide analysis of zebrafish protein-coding gene function

          Ross N W Kettleborough, Elisabeth Busch-Nentwich, Steven Harvey … (2013)
          Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at an enormous rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in vertebrate model organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches 1-3 and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes 3,4 , this number falls significantly short of all >22,000 mouse protein-coding genes 5 . Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning 6 , insertional mutagenesis 7-9 , antisense morpholino oligonucleotides 10 , targeted re-sequencing 11-13 and zinc finger and TAL endonucleases 14-17 have made significant contributions to our understanding of the biological activity of vertebrate genes, but the number of genes studied again falls well short of the >26,000 zebrafish protein-coding genes 18 . Importantly, for both mice and zebrafish, none of these strategies is particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Enabled by a well-annotated zebrafish reference genome sequence 18,19 , high-throughput sequencing and efficient chemical mutagenesis, we describe an active project that aims to identify and phenotype disruptive mutations in every zebrafish protein-coding gene. Thus far we have identified potentially disruptive mutations in more than 38% of all known protein coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.
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            Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression.

            H Baier, Camila Castro, Jonathan Taylor … (2004)
            Rodent seizure models have significantly contributed to our basic understanding of epilepsy. However, medically intractable forms of epilepsy persist and the fundamental mechanisms underlying this disease remain unclear. Here we show that seizures can be elicited in a simple vertebrate system e.g. zebrafish larvae (Danio rerio). Exposure to a common convulsant agent (pentylenetetrazole, PTZ) induced a stereotyped and concentration-dependent sequence of behavioral changes culminating in clonus-like convulsions. Extracellular recordings from fish optic tectum revealed ictal and interictal-like electrographic discharges after application of PTZ, which could be blocked by tetrodotoxin or glutamate receptor antagonists. Epileptiform discharges were suppressed by commonly used antiepileptic drugs, valproate and diazepam, in a concentration-dependent manner. Up-regulation of c-fos expression was also observed in CNS structures of zebrafish exposed to PTZ. Taken together, these results demonstrate that chemically-induced seizures in zebrafish exhibit behavioral, electrographic, and molecular changes that would be expected from a rodent seizure model. Therefore, zebrafish larvae represent a powerful new system to study the underlying basis of seizure generation, epilepsy and epileptogenesis.
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              An evaluation of the two-dimensional Gabor filter model of simple receptive fields in cat striate cortex.

              J. Jones, L A Palmer (1987)
              1. Using the two-dimensional (2D) spatial and spectral response profiles described in the previous two reports, we test Daugman's generalization of Marcelja's hypothesis that simple receptive fields belong to a class of linear spatial filters analogous to those described by Gabor and referred to here as 2D Gabor filters. 2. In the space domain, we found 2D Gabor filters that fit the 2D spatial response profile of each simple cell in the least-squared error sense (with a simplex algorithm), and we show that the residual error is devoid of spatial structure and statistically indistinguishable from random error. 3. Although a rigorous statistical approach was not possible with our spectral data, we also found a Gabor function that fit the 2D spectral response profile of each simple cell and observed that the residual errors are everywhere small and unstructured. 4. As an assay of spatial linearity in two dimensions, on which the applicability of Gabor theory is dependent, we compare the filter parameters estimated from the independent 2D spatial and spectral measurements described above. Estimates of most parameters from the two domains are highly correlated, indicating that assumptions about spatial linearity are valid. 5. Finally, we show that the functional form of the 2D Gabor filter provides a concise mathematical expression, which incorporates the important spatial characteristics of simple receptive fields demonstrated in the previous two reports. Prominent here are 1) Cartesian separable spatial response profiles, 2) spatial receptive fields with staggered subregion placement, 3) Cartesian separable spectral response profiles, 4) spectral response profiles with axes of symmetry not including the origin, and 5) the uniform distribution of spatial phase angles. 6. We conclude that the Gabor function provides a useful and reasonably accurate description of most spatial aspects of simple receptive fields. Thus it seems that an optimal strategy has evolved for sampling images simultaneously in the 2D spatial and spatial frequency domains.
              Article 0 comments Cited 169 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Peter M. Eimon: peter.eimon@gmail.com
                Mehmet Fatih Yanik: yanik@ethz.ch
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 15 January 2018
                Publication date PMC-release: 15 January 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 219
                Affiliations
                [1 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Massachusetts Institute of Technology, ; 77 Massachusetts Avenue, Cambridge, MA 02139 USA
                [2 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, UZH/ETH Irchel Campus, ; Y17-L76, Winterthurerstrasse 190, 8057 Zürich, Switzerland
                [3 ]Intellimedix, Cambridge, MA 02139 USA
                [4 ]ISNI 0000 0001 2097 4943, GRID grid.213917.f, Georgia Institute of Technology, ; 950 Atlantic Drive, Room 2151, Atlanta, GA 30332 USA
                [5 ]GRID grid.479532.e, Present Address: Axcella Health, ; 840 Memorial Dr, Cambridge, MA 02139 USA
                Author information
                http://orcid.org/0000-0003-4028-8443
                Article
                Publisher ID: 2404
                DOI: 10.1038/s41467-017-02404-4
                PMC ID: 5768723
                PubMed ID: 29335539
                SO-VID: 64ff0c96-5a94-4f81-a72f-a236bfc8df9a
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 16 March 2017
                Date accepted : 25 November 2017
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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