Kainate receptor-induced ectopic spiking of CA3 pyramidal neurons initiates network bursts in neonatal hippocampus.

Kainate receptors (KARs) are expressed at high levels in the brain during early development and may be critical for the proper development of neuronal networks. Here we elucidated a physiological role of high-affinity KARs in developing hippocampal network by studying the effects of 25-100 nM kainate (KA) on intrinsic network activity in slice preparations. Whereas 100 nM KA resulted in hyperexcitability of the network and the disruption of natural activity patterns, ≤ 50 nM KA concentrations enhanced the initiation of network bursts yet preserved the characteristic patterns of endogenous activity. This was not dependent on changes in GABAergic transmission or on activation of GluK1 subunit containing KARs. However, the activation of high-affinity KARs increased glutamatergic drive by promoting spontaneous firing of CA3 pyramidal neurons without affecting action potential independent glutamate release. This was not because of changes in the intrinsic somatic properties of pyramidal neurons but seemed to reside in an electrically remote site, most probably in an axonal compartment. Although application of KAR agonists has mainly been used to study pathological type of network activities, this study provides a novel mechanism by which endogenous activity of KARs can modulate intrinsic activities of the emerging neuronal network in a physiologically relevant manner. The results support recent studies that KARs play a central role in the activity-dependent maturation of synaptic circuitries.

High firing rate of neonatal hippocampal interneurons is caused by attenuation of afterhyperpolarizing potassium currents by tonically active kainate receptors.

In the neonatal hippocampus, the activity of interneurons shapes early network bursts that are important for the establishment of neuronal connectivity. However, mechanisms controlling the firing of immature interneurons remain elusive. We now show that the spontaneous firing rate of CA3 stratum lucidum interneurons markedly decreases during early postnatal development because of changes in the properties of GluK1 (formerly known as GluR5) subunit-containing kainate receptors (KARs). In the neonate, activation of KARs by ambient glutamate exerts a tonic inhibition of the medium-duration afterhyperpolarization (mAHP) by a G-protein-dependent mechanism, permitting a high interneuronal firing rate. During development, the amplitude of the apamine-sensitive K+ currents responsible for the mAHP increases dramatically because of decoupling between KAR activation and mAHP modulation, leading to decreased interneuronal firing. The developmental shift in the KAR function and its consequences on interneuronal activity are likely to have a fundamental role in the maturation of the synchronous neuronal oscillations typical for adult hippocampal circuitry.