Expression of GluK1c underlies the developmental switch in presynaptic kainate receptor function

Aino Vesikansa, Prasanna Sakha, Juha Kuja-Panula, Svetlana Molchanova, Claudio Rivera, Henri J. Huttunen, Heikki Rauvala, Tomi Taira, Sari E. Lauri
2012 Scientific Reports  
Kainate-type glutamate receptors (KARs) regulate synaptic transmission and neuronal excitability via multiple mechanisms, depending on their subunit composition. Presynaptic KARs tonically depress glutamatergic transmission during restricted period of synapse development; however, the molecular basis behind this effect is unknown. Here, we show that the developmental and cell-type specific expression pattern of a KAR subunit splice variant, GluK1c, corresponds to the immature-type KAR activity
more » ... n the hippocampus. GluK1c localizes to dendritic contact sites at distal axons, the distal targeting being promoted by heteromerization with the subunit GluK4. Presynaptic expression of GluK1c strongly suppresses glutamatergic transmission in cell-pairs in vitro and mimics the immature-type KAR activity at CA3-CA1 synapses in vivo, at a developmental stage when the endogenous expression is already downregulated. These data support a central role for GluK1c in mediating tonic inhibition of glutamate release and the consequent effects on excitability and activity-dependent fine-tuning of the developing hippocampal circuitry. K ainate-type of glutamate receptors (KARs) consist of homo-or heteromeric combinations of five subunits (GluK1-5; previously known as GluR5-7, KA1 and KA2; 1 ) and act as key modulators of neuronal function in several areas of the brain. The precise role of KARs is strictly dependent on their subcellular localization and subunit composition that varies between cell types and during development. At the presynaptic compartment, KARs regulate transmitter release at both glutamatergic and GABAergic synapses and control presynaptic forms of short-and long-term synaptic plasticity 2-4 . In the neonate CA1, presynaptic KARs are tonically activated by ambient glutamate, causing continuous physiological suppression of glutamate release 5 . In addition to the physiological relevance in controlling information transfer at the developing hippocampal circuitry, tonic KAR activity is critical for formation and maturation of CA3-CA1 glutamatergic synapses 6 . The immature-type KARs are gradually lost during second postnatal week in parallel with the activity-dependent maturation of the neuronal circuitry, and are replaced with adult -type KARs lacking tonic activity and with distinct downstream signaling mechanisms 5, 7, 8 . Many of the functions ascribed for KARs at developing glutamatergic synapses are sensitive to GluK1-subunit specific agonists and antagonists 5-9 . The molecular composition of these receptors could be diverse since these pharmacological tools act on both homomeric and heteromeric receptors containing the GluK1 subunit 10 . In addition, GluK1 subunits exist as three C-terminal splice variants (named GluK1a, GluK1b and GluK1c), which differ in their tissue-specific expression pattern, membrane delivery and protein interactions 11,12 . Heteromerization of GluK1 with the subunits GluK4-5 provides KARs with higher agonist affinity 13-15 , necessary for activation by physiological concentrations of glutamate in the immature brain 5 . However, the cell-type specific expression profile or the developmental regulation of various GluK1 splice variants, as homomeric receptors or as heteromeric combinations with other KAR subunits is not known. Here we show that in the developing hippocampus, the splice variants GluK1b and GluK1c are preferentially expressed in interneurons and pyramidal cells, respectively. GluK1c strongly co-localizes with the high-affinity subunit GluK4, which promotes its targeting to distal neuronal processes. We further demonstrate that expression of GluK1c at CA3 pyramidal neurons is sufficient to mimic the immature-type KAR activity at a developmental stage when the endogenous expression is already lost. These findings strongly suggest that the tonic SUBJECT AREAS: RECEPTORS DEVELOPMENT SYNAPTIC TRANSMISSION PLASTICITY
doi:10.1038/srep00310 pmid:22413061 pmcid:PMC3298885 fatcat:b6jeug3x5je3zf5qi3achkul5u