Localization and function of pre‐ and postsynaptic kainate receptors in the rat globus pallidus

Abstract

Kainate receptors (KARs) are widely expressed the basal ganglia. In this study, we used electron microscopic immunocytochemistry and whole-cell recording techniques to examine the localization and function of KARs in the rat globus pallidus (GP). Dendrites were the most common immunoreactive elements, while terminals forming symmetric or asymmetric synapses and unmyelinated axons comprised most of the presynaptic labeling. To determine whether synaptically released glutamate activates KARs, we recorded excitatory postsynaptic currents (EPSCs) in the GP following single-pulse stimulation of the internal capsule. 4-(8-Methyl-9H-1,3-dioxolo[4,5 h]{2,3}benzodiazepine-5-yl)-benzenamine hydrochloride (GYKI 52466, 100 microm), an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, reduced but did not completely block evoked EPSCs. The remaining EPSC component was mediated through activation of KARs because it was abolished by 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX), an AMPA/KAR antagonist. The rise time (10-90%) and decay time constant (tau) for those EPSCs were longer than those of AMPA-mediated EPSCs recorded before GYKI 52466 application. KAR activation inhibited EPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio, suggesting a presynaptic action of KAR. KAR inhibition of EPSCs was blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or the protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation has dual effects on glutamatergic transmission in the rat GP: (1) it mediates small-amplitude EPSCs; and (2) it reduces glutamatergic synaptic transmission through a presynaptic G-protein coupled, PKC-dependent, metabotropic mechanism. These findings provide evidence for the multifarious functions of KARs in regulating synaptic transmission, and open up the possibility for the development of pharmacotherapies to reduce the hyperactive subthalamofugal projection in Parkinson's disease.

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

“…The localization of KA receptors at the EM level has been studied in the striatum and GP (Charara et al, 1999;Kieval et al, 2001;Kane-Jackson and Smith, 2003;Jin and Smith, 2005;Jin et al, 2006), but not in other basal ganglia. In the monkey striatum, pre-and postembedding immunogold methods have revealed that the largest proportion of GluR6/7 and KA2 plasma membrane-bound subunits is located at extrasynaptic sites, while only one third is located at glutamatergic synapses ), a strikingly different pattern from that of AMPA and NMDA receptors distributions (Bernard et al, 1997;Bernard and Bolam, 1998;Fujiyama et al, 2004).…”

Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex

“…Although not universally present, functional postsynaptic KARs have been shown to be present in a variety of cell types such as cerebellar granule cells and Golgi cells (Bureau et al, 2000), retinal bipolar cells (DeVries and Schwartz, 1999), neurons of the superficial dorsal horn (Li et al, 1999), lateral superior olive (Vitten et al, 2004), motor & somatosensory cortex (Kidd and Isaac, 1999, Ali, 2003, Eder et al, 2003, the amygdala , the anterior cingulate cortex (Wu et al, 2005), the globus pallidus (Jin et al, 2006), and a variety of neurons in the hippocampus (Castillo et al, 1997, Vignes and Collingridge, 1997, Cossart et al, 1998, Frerking et al, 1998, Frerking et al, 1999, Cossart et al, 2002. In accordance with these previous studies, KAR mediated EPSCs in the mEC were defined by their resistance to 100 μM GYKI 52466 or 1 μM NBQX, their small amplitude and slow kinetics, the ability to summate during high frequency stimulation, and their inhibition by 10-50 μM CNQX.…”

“…These receptors have been shown to both mediate and modulate synaptic transmission in both the central and peripheral nervous system (for reviews see (Chittajallu et al, 1999, Frerking and Nicoll, 2000, Lerma et al, 2001, Lerma, 2003, Lerma, 2006, Pinheiro and Mulle, 2006). Regarding the mediation of synaptic transmission, functional postsynaptic KARs have been demonstrated in a variety of cell types (Castillo et al, 1997, Vignes and Collingridge, 1997, Cossart et al, 1998, Frerking et al, 1998, DeVries and Schwartz, 1999, Kidd and Isaac, 1999, Li et al, 1999, Bureau et al, 2000, Cossart et al, 2002, Ali, 2003, Eder et al, 2003, Vitten et al, 2004, Wu et al, 2005, Jin et al, 2006 and may impose unique integrative properties to neurons (Frerking and Ohliger-Frerking, 2002). Furthermore, the expression of postsynaptic KARs has been shown to be restricted in a cellular and subcellular manner.…”

Endoplasmic Reticulum Is a Key Organella in Bradykinin-Triggered ATP Release From Cultured Smooth Muscle Cells

“…The extracellular release of ATP was almost completely blocked by U-73122, a phospholipase C inhibitor; thapsigargin, a Ca 2+ -ATPase inhibitor; and BAPTA / AM, an intracellular Ca 2+ chelator. Furthermore, the release of ATP was markedly reduced by N-ethylmaleimide (NEM), a G-protein inhibitor (24,25) (Fig. 2A).…”