Twenty Years of SynGAP Research: From Synapses to Cognition

Gamache, Timothy R; Araki, Yasuhisa; Huganir, Richard L.

doi:10.1523/jneurosci.0420-19.2020

Cited by 118 publications

(127 citation statements)

References 96 publications

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“…Furthermore, our morphometric data suggests that syngap1b tup1 mutants exhibit significantly increased head and eye sizes at 3 dpf, counter to the findings in zebrafish morphants [19], mutant mice [41], and patients [29] that exhibit reduced brain ventricle sizes and mild microcephaly. It is important to note that microcephaly phenotypes have low penetrance in SYNGAP1 zebrafish morphants and are identified in 30% of human patients carrying heterozygous mutations of the gene [42].…”

Section: Discussioncontrasting

confidence: 79%

“…We assayed a stable mutant line of syngap1b as a proof of concept, a gene that had previously been studied using morpholinos [19]. We noted a skewed distribution of genotypes (reduced hom and het alleles versus WT) after subjecting them to our combined phenotyping assay, suggesting that mutant larvae have reduced viability, in line with perinatal lethality of hom null mutations observed in Syngap1 mouse models [29]. Our het syngap1b tup1/+ mutants moved greater distances over 1 h in the presence of PTZ versus WT, suggesting they may be experiencing enhanced seizures, consistent with spontaneous seizures in syngap1b morphants [19].…”

Section: Discussionmentioning

confidence: 82%

“…To test this, we used CRISPR to generate a null mutant zebrafish model of human SYNGAP1, a gene encoding neuronal Ras and Rap GTPase-activating proteins. Heterozygous mutations of SYNGAP1, important for synaptogenesis and regulation of excitatory synapses [27,28], are associated with neurodevelopmental disorders, including epilepsy, ASD, and ID [29]. A previous study using morpholinos targeting mRNAs encoding the two zebrafish orthologs of the gene (Figure S5A) syngap1a and syngap1b showed malformed mid-and hindbrain (48 hours post fertilization (hpf)), developmental delay (48 hpf), and spontaneous seizures, correlated to an observed decrease in GABA neurons in the mid-and hindbrain, specific to the syngap1b morphant larvae at 3 dpf [19].…”

Section: Proof Of Concept Using a Stable Zebrafish Mutant Model Of Symentioning

confidence: 99%

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Assessment of autism zebrafish mutant models using a high-throughput larval phenotyping platform

Colón-Rodríguez

Uribe-Salazar²,

Weyenberg³

et al. 2020

Preprint

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In recent years zebrafish have become commonly used as a model for studying human traits and disorders. Their small size, high fecundity, and rapid development allow for more high-throughput experiments compared to other vertebrate models. Given that zebrafish share >70% gene homologs with humans and their genomes can be readily edited using highly efficient CRISPR methods, we are now able to rapidly generate mutations impacting practically any gene of interest. Unfortunately, our ability to phenotype mutant larvae has not kept pace. To address this challenge, we have developed a protocol that obtains multiple phenotypic measurements from individual zebrafish larvae in an automated and parallel fashion, including morphological features (i.e., body length, eye area, and head size) and movement/behavior. By assaying wild-type zebrafish in a variety of conditions, we determined optimal parameters that avoid significant developmental defects or physical damage; these include morphological imaging of larvae at two time points (3 days post fertilization (dpf) and 5 dpf) coupled with motion tracking of behavior at 5 dpf. As a proof-of-principle, we tested our approach on two novel CRISPR-generated mutant zebrafish lines carrying predicted null-alleles of syngap1b and slc7a5, orthologs to two human genes implicated in autism-spectrum disorder, intellectual disability, and epilepsy. Using our optimized high-throughput phenotyping protocol, we recapitulated previously published results from mouse and zebrafish models of these candidate genes. In summary, we describe a rapid parallel pipeline to characterize morphological and behavioral features of individual larvae in a robust and consistent fashion, thereby improving our ability to better identify genes important in human traits and disorders.AUTHOR SUMMARYZebrafish (Danio rerio) are a well-established model organism for the study of neurodevelopmental disorders. Due to their small size, fast reproduction, and genetic homology with humans, zebrafish have been widely used for characterizing and screening candidate genes for many disorders, including autism-spectrum disorder, intellectual disability, and epilepsy. Although several studies have described the use of high-throughput morphological and behavioral assays, few combine multiple assays in a single zebrafish larva. Here, we optimized a platform to characterize morphometric features at two developmental time points in addition to behavioral traits of zebrafish larvae. We then used this approach to characterize two autism candidate genes (SYNGAP1 and SLC7A5) in two CRISPR-generated zebrafish null mutant models we developed in house. These data recapitulate previously published results related to enhanced seizure activity, while identifying additional defects not previously reported. We propose that our phenotyping platform represents a feasible method for maximizing the use of single zebrafish larvae in the characterization of additional mutants relevant to neurodevelopmental disorders.

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 82%

Section: Proof Of Concept Using a Stable Zebrafish Mutant Model Of Symentioning

confidence: 99%

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Assessment of autism zebrafish mutant models using a high-throughput larval phenotyping platform

Colón-Rodríguez

Uribe-Salazar²,

Weyenberg³

et al. 2020

Preprint

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“…Communications between neurons and glia occur largely via synapses, nanostructures of about 20–40 nm, in one or more dimensions. Synapses are biological nanostructures which play essential roles in the CNS functions [ 11 , 12 , 13 ]. The neuronal cell body (soma) has a fine tubular process called an axon which conducts electrical impulses from the soma to the axon terminals (presynaptic boutons).…”

Section: Neurons and Glial Cells In The Brainmentioning

confidence: 99%

Dendrimers as Modulators of Brain Cells

2020

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Nanostructured hyperbranched macromolecules have been extensively studied at the chemical, physical and morphological levels. The cellular structural and functional complexity of neural cells and their cross-talk have made it rather difficult to evaluate dendrimer effects in a mixed population of glial cells and neurons. Thus, we are at a relatively early stage of bench-to-bedside translation, and this is due mainly to the lack of data valuable for clinical investigations. It is only recently that techniques have become available that allow for analyses of biological processes inside the living cells, at the nanoscale, in real time. This review summarizes the essential properties of neural cells and dendrimers, and provides a cross-section of biological, pre-clinical and early clinical studies, where dendrimers were used as nanocarriers. It also highlights some examples of biological studies employing dendritic polyglycerol sulfates and their effects on glia and neurons. It is the aim of this review to encourage young scientists to advance mechanistic and technological approaches in dendrimer research so that these extremely versatile and attractive nanostructures gain even greater recognition in translational medicine.

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“…Investigating the electrical activity of the brain Electroencephalography (EEG) is of course widely used as an investigation in people with neurological conditions such as epilepsy. People with SYNGAP1 variants have been shown to have a variety of epileptiform activity on EEG as well as other abnormalities (Gamache 2020). EEG can also be done in rodents and, as with humans, pairing it with a video recording of the subject is particularly informative, especially if seizure activity is suspected.…”

Section: Studying Biochemical Pathwaysmentioning

confidence: 99%

Demystifying neuroscience laboratory techniques used to investigate single-gene disorders

Mizen¹,

Stanfield²

2020

BJPsych advances

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SUMMARY There is considerable work being carried out in neuroscientific laboratories to delineate the mechanisms underlying single-gene disorders, particularly those related to intellectual disability and autism spectrum disorder. Many clinicians will have little if any direct experience of this type of work and so find the procedures and terminology difficult to understand. This article describes some of the laboratory techniques used and their increasing relevance to clinical practice. It is pitched for clinicians with little or no laboratory science background.

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Twenty Years of SynGAP Research: From Synapses to Cognition

Cited by 118 publications

References 96 publications

Assessment of autism zebrafish mutant models using a high-throughput larval phenotyping platform

Assessment of autism zebrafish mutant models using a high-throughput larval phenotyping platform

Dendrimers as Modulators of Brain Cells

Demystifying neuroscience laboratory techniques used to investigate single-gene disorders

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