Domoic acid suppresses hyperexcitation in the network due to activation of kainate receptors of GABAergic neurons

Abstract

Kainate receptors play an important role in the brain. They contribute to postsynaptic depolarization, modulate the release of neurotransmitters such as GABA and glutamate, affect the development of the neuronal network. At the same time, their functions depend not only on the type of neuron expressing them but also on their localization (pre- or postsynaptic). It has been shown in present work that activation of kainate receptors by domoic acid stimulates the secretion of both glutamate and GABA. This effect is observed at a concentration of 100 nM. At higher levels (200–500 nM), domoic acid selectively activates a specific population of GABAergic neurons. The peculiarity of these neurons is increased excitability in the network. This phenomenon can be explained by the weak GABA(A)R-mediated inhibition, as well as by the lower activation threshold of voltage-gated channels. Moreover, activation of these GABAergic neurons by domoic acid leads to the suppression of activity in the network under ammonium-induced hyperexcitation. As shown by inhibitory analysis, this effect is mediated by GABA(A) receptors. The obtained data may be of interest since the suppression of hyperexcitation via the selective activation of GABAergic neurons can be considered as a new potential approach to the treatment of diseases accompanied by increased neuronal activity such as epilepsy, ischemia and hepatic encephalopathy.