[Na.sup.+] channel-mediated [Ca.sup.2+] entry leads to glutamate secretion in mouse neocortical preplate

Before synaptogenesis, early excitability implicating voltage-dependent and transmitter-activated channels is known to be crucial for neuronal development. We previously showed that preplate (PP) neurons of the mouse neocortex express functional [Na.sup.+] channels as early as embryonic day 12. In this study, we investigated the role of these [Na.sup.+] channels in signaling during early development. In the neocortex of embryonic-day-13 mice, activation of Nat channels with veratridine induced a large [Ca.sup.2+] response throughout the neocortex, even in cell populations that lack the [Na.sup.+] channel. This [Na.sup.+]-dependent [Ca.sup.2+] activity requires external [Ca.sup.2+] and is completely blocked by inhibitors of [Na.sup.+]/[Ca.sup.2+] exchangers. Moreover, veratridine-induced [Ca.sup.2+] increase coincides with a burst of exocytosis in the PP. In parallel, we show that Nat channel stimulation enhances glutamate secretion in the neocortical wall. Released glutamate triggers further [Ca.sup.2+] response in PP and ventricular zone, as indicated by the decreased response to veratridine in the presence of [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NMDA-receptor inhibitors. Therefore, the combined activation of the Nat channel and the [Na.sup.+]/[Ca.sup.2+] exchanger triggers [Ca.sup.2+] signaling in the PP neurons, leading to glutamate secretion, which amplifies the signal and serves as an autocrine/paracrine transmitter before functional synapses are formed in the neocortex. Membrane depolarization induced by glycine receptors activation could be one physiological activator of this [Na.sup.+] channel-dependent pathway. [Ca.sup.2+] signaling | [Na.sup.+]/[Ca.sup.2+] exchanger | exocytosis | neurogenesis