The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex

Spratt, Perry W.E.; Ben-Shalom, Roy; Keeshen, Caroline M.; Burke, Kenneth; Clarkson, Rebecca L.; Sanders, Stephan; Bender, Kevin J.

doi:10.1016/j.neuron.2019.05.037

Cited by 159 publications

(276 citation statements)

References 89 publications

(126 reference statements)

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“…NaV channels contribute to AP backpropagation. Thus, examination of the second derivative of the AP and quantification of the AIS and somatodendritic portions, can provide an indirect estimate of sodium conduction (Hu et al, 2009;Spratt et al, 2019). Here, examination of the second derivative of the eAPs showed increased acceleration of the late, somatodendritic portion (Fig.…”

Section: Dsmentioning

confidence: 82%

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Almog

Brusel

Anderson

et al. 2019

Preprint

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Dravet syndrome (Dravet) epilepsy begins with febrile seizures followed by worsening to refractory seizures, with some improvement and stabilization toward adolescence. The neuronal basis of Dravet is debatable, with evidence favoring reduced inhibition or enhanced excitation. Focusing on the firing properties of hippocampal CA1 pyramidal neurons and oriens-lacunosum moleculare (O-LM) interneurons, we provide a comprehensive analysis of the activity of both cell types through the febrile, worsening and stabilization stages. Our data indicate a temporary increase in the excitability of CA1 pyramidal neurons during the febrile stage, which is fully reversed by the onset of spontaneous seizures. In contrast, reduced function of O-LM interneurons persisted from the febrile through the stabilization stages, with the greatest impairment of excitability occurring during the worsening stage. Thus, both excitatory and inhibitory neurons contribute to Dravet, indicating complex and reciprocal pathophysiological neuronal changes during the different stages of the disease.

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Section: Dsmentioning

confidence: 82%

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Almog

Brusel

Anderson

et al. 2019

Preprint

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“…Unsurprisingly, given their close association with ankyrin-G, neurofascin, Na v 1, and K v 7 channels all show periodic arrangements in the AIS or NoR (D'Este et al, 2017;Leterrier et al, 2015;Xu et al, 2013). Likewise, mutations in these proteins have been linked to converging or overlapping pathologies, such as epilepsy, ASD, and bipolar disorder (Kloth et al, 2017;Singh et al, 1998;Spratt et al, 2019;Wirgenes et al, 2014).…”

Section: Ankyrin Binding Partnersmentioning

confidence: 99%

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Lorenzo

2020

Cytoskeleton

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The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

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“…Canonical knock-out (null) of Scn2a in mice is perinatal lethal, therefore current studies focus on heterozygous Scn2a knockout mice (Scn2a +/− ) as the main model for study, which display only mild behavioral abnormalities. Scn2a +/− mice show little differences from wild-type (WT) mice in body weight, olfactory, auditory startle, thermal sensitivity, nesting, and marble burying [10] [11] [12] [13]. We reasoned that if we can substantially reduce the Scn2a expression level without eliminating it completely, the residual Scn2a protein may allow the mice to survive and to exhibit more severe phenotypes in adulthood than is observed in heterozygous knockout mice, thereby providing a novel model for the study of Scn2a deficiencyrelated biological processes.…”

Section: Introductionmentioning

confidence: 99%

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

Eaton

Zhang

et al. 2020

Preprint

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Recent large-scale genomic studies have revealed SCN2A as one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability. SCN2A encodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) of Scn2a is perinatal lethal, whereas heterozygous knockout of Scn2a results in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction of Scn2a expression, we characterized a Scn2a deficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-function SCN2A disorders. This model produces viable homozygous mice (Scn2a gtKO/gtKO ) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. Although Scn2a gtKO/gtKO adult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novel Scn2a gene trap knockout mouse thus provides a unique model to study pathophysiology associated with Scn2a deficiency.

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The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex

Cited by 159 publications

References 89 publications

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

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