Presynaptically silent synapses are modulated by the density of surrounding astrocytes

Oyabu, Kohei; Takeda, Kotomi; Kawano, Hiroyuki; Kubota, Kaori; Harata, Nobutoshi; Katsurabayashi, Shutaro; Iwasaki, Katsunori

doi:10.1016/j.jphs.2020.07.009

“…We used autapse culture preparations, which are co-cultured preparations of dot-cultured astrocytes and a single neuron, for the synaptic function analysis 32 – 36 . The axons of autapse neurons form many synapses (autapses) to their cell bodies and dendrites, without any synaptic contacts from other neurons.…”

Section: Methodsmentioning

confidence: 99%

“…The sizes and numbers of synaptic puncta were detected using ImageJ software. The procedures used to analyze the synaptic puncta have been published previously 36 , 37 .…”

Section: Methodsmentioning

confidence: 99%

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

Uchino

¹

,

Kawano

²

,

Tanaka

³

et al. 2021

Sci Rep

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Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

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“…We used autapse culture preparations, which are co-cultured preparations of dot-cultured astrocytes and a single neuron, for the synaptic function analysis 15,16,17,18,19 . The axons of autapse neurons form many synapses (autapses) to their cell bodies and dendrites, without any synaptic contacts from other neurons.…”

Section: Autapse Culture Specimens Of Single Neuronsmentioning

confidence: 99%

“…The sizes and numbers of synaptic puncta were detected using ImageJ software. The procedures used to analyze the synaptic puncta have been published previously 19,20 .…”

Section: Image Acquisition and Quanti Cationmentioning

confidence: 99%

The Excitatory/Inhibitory Balance of Synaptic Transmission Is Impaired at Higher Extracellular Ca2+ Concentrations in Scn1a+/− Mouse Model of Dravet Syndrome

Uchino

¹

,

Kawano

²

,

Tanaka

³

et al. 2021

Preprint

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0

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Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

show abstract

“…However, astrocytes are found throughout the central nervous system and play an essential role in neuronal function (13). For example, we have demonstrated that the long-term culture of astrocytes and changes in astrocyte density can alter neuronal growth and synaptic transmission (14, 15). Advances in Ca 2+ imaging methods have revealed that astrocytes are excitable cells that exhibit intracellular Ca 2+ signaling (16).…”

Section: Introductionmentioning

confidence: 99%

Astrocyte Ca²⁺ Signaling is Facilitated in an Scn1a^+/− Mouse Model of Dravet Syndrome

Uchino

¹

,

Ikezawa

²

,

Tanaka

³

et al. 2021

Preprint

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Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A, which encodes a subunit of the voltage-gated sodium channel, Nav1.1, in neurons. The roles played by astrocytes, the most abundant glial cell type in the brain, have been investigated in the pathogenesis of epilepsy; however, the specific involvement of astrocytes in DS has not been clarified. In this study, we evaluated Ca2+ signaling in astrocytes using genetically modified mice that have a loss-of-function mutation in Scn1a. We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/− astrocytes. In addition, ATP-induced transient Ca2+ influx and the slope of Ca2+ spiking were also increased in Scn1a+/− astrocytes. These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS.

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Presynaptically silent synapses are modulated by the density of surrounding astrocytes

Cited by 12 publications

References 29 publications

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

The Excitatory/Inhibitory Balance of Synaptic Transmission Is Impaired at Higher Extracellular Ca2+ Concentrations in Scn1a+/− Mouse Model of Dravet Syndrome

Astrocyte Ca²⁺ Signaling is Facilitated in an Scn1a^+/− Mouse Model of Dravet Syndrome

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Presynaptically silent synapses are modulated by the density of surrounding astrocytes

Cited by 12 publications

References 29 publications

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

Inhibitory synaptic transmission is impaired at higher extracellular Ca2+ concentrations in Scn1a+/− mouse model of Dravet syndrome

The Excitatory/Inhibitory Balance of Synaptic Transmission Is Impaired at Higher Extracellular Ca2+ Concentrations in Scn1a+/− Mouse Model of Dravet Syndrome

Astrocyte Ca2+ Signaling is Facilitated in an Scn1a+/− Mouse Model of Dravet Syndrome

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Astrocyte Ca²⁺ Signaling is Facilitated in an Scn1a^+/− Mouse Model of Dravet Syndrome