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

<jats:title>Abstract</jats:title> <jats:p>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 <jats:italic>SCN1A</jats:italic> gene, which encodes a subunit of Na<jats:sup>+</jats:sup> 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 <jats:italic>Scn1a</jats:italic> knock-in neurons (<jats:italic>Scn1a</jats:italic><jats:sup>+/−</jats:sup> neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in <jats:italic>Scn1a</jats:italic><jats:sup>+/−</jats:sup> neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in <jats:italic>Scn1a</jats:italic><jats:sup>+/−</jats:sup> neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca<jats:sup>2+</jats:sup> concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in <jats:italic>Scn1a</jats:italic><jats:sup>+/−</jats:sup> neurons, while the sensitivity of inhibitory synapses to extracellular Ca<jats:sup>2+</jats:sup> concentrations is markedly increased. These data suggest that Ca<jats:sup>2+</jats:sup> tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.</jats:p>