High Firing Rate of Neonatal Hippocampal Interneurons Is Caused by Attenuation of Afterhyperpolarizing Potassium Currents by Tonically Active Kainate Receptors

Abstract

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-proteindependent mechanism, permitting a high interneuronal firing rate. During development, the amplitude of the apamine-sensitive K ϩ 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.

A Proteomic Analysis Reveals the Interaction of GluK1 Ionotropic Kainate Receptor Subunits with Go Proteins

“…Also, data show that metabotropic signaling remained in GluK4/GluK5 double-KO mice (Fernandes et al, 2009). Similarly, recent experiments suggested the involvement of GluK1 in the metabotropic control of glutamate release (Segerstråle et al, 2010;Salmen et al, 2012). Therefore, our data clarify that the KAR subunit capable of activating a G-protein is GluK1 b and that this G-protein corresponds to the G␣o type, which is consistent with earlier indirect data showing that GluK1 subunits can reproduce noncanonical KAR signaling in a heterologous system (Rivera et al, 2007).…”

“…Immunoprecipitation was performed as described previously (Selak et al, 2009). Briefly, lysates from cell lines cotransfected with myc-GluK1 b and flag-G␣o were precleared by incubating with protein A (GE Healthcare) or protein-G Sepharose (SigmaAldrich) in 20 mM MOPS, pH 7.0, 150 mM KCl, and 1% Triton X-100 for 1 h at 4°C, to eliminate nonspecific binding.…”

“…Myc-GluK1 2b VCT , MycGluK1 2 ⌬C VCT , Myc-GluK5 VNT , and Myc-GluK4 VNT were generated by fusing the C-terminal domain (V155) of Venus (VCT) to the C terminus of myc-GluK1 2b , myc-GluK1⌬C, or myc-GluK5, respectively. MycGluK4, Myc-GluK5, and myc-GluK5⌬C were also fused to the N-terminal domain of Venus (V154m9; VNT) as described previously (Selak et al, 2009). For the G␣o subunit, both parts of the Venus protein were fused to the G␣o protein in the loop after residue Val 93 , as described previously (Ayoub et al, 2009), generating G␣o VNT or G␣o VCT .…”

“…Several proteins have been identified that interact with KARs, particularly with their GluK2 subunits (Coussen and Mulle, 2006;Martin et al, 2007;Wilkinson et al, 2008;Tomita and Castillo, 2012), and to a lesser extent with GluK1 (Hirbec et al, 2003) and GluK5 subunits (Vivithanaporn et al, 2006;Selak et al, 2009;Marques et al, 2013). Indeed, PICK1 (protein interacting with C-kinase 1), SNAP25 (synaptosomal-associated protein of 25 kDa), GRIP (glutamate receptor-interacting protein), SUMO-1 (small ubiquitin-related modifier-1), calcineurin, VILIP (visinin-like protein), Profilin II, and Neto 1 and 2 are among those proteins now known to interact with KAR subunits (for review, see Lerma and Marques, 2013).…”

Dissecting functional connectivity of neuronal microcircuits: experimental and theoretical insights

“…In addition, the links between immature neurons are not only less developed, but also most often radically different from adult ones in many important ways. Some of these differences include: (i) synapses can be silent during early stages of development [93]; (ii) gap junctions are abundant and mediate neuronal synchronization [79,94,95]; (iii) GABA, the main inhibitory transmitter in the adult brain, is depolarizing at early stages in development as a result of higher intracellular chloride concentrations [96]; (iv) tonic currents provide membrane depolarization [77,[97][98][99]; and (v) action potentials are often immature and neurons have a higher tendency to be active in bursts due to different intrinsic properties [80]. In other words, developing cortical networks are not just smaller and poorly connected adult circuits but are very different entities in many ways, and these limitations need to be kept in mind when extrapolating any data obtained from developing networks to the functional connectivity of mature neuronal networks.…”