Characterisation of the effects of ATPA, a GLUK5 kainate receptor agonist, on GABAergic synaptic transmission in the CA1 region of rat hippocampal slices
Introduction
l-glutamate mediates the majority of fast excitatory neurotransmission in the central nervous system (CNS). Pharmacological studies first demonstrated the existence of kainate receptors (Davies et al., 1979, Davies and Watkins, 1979, McLennan and Lodge, 1979, Agrawal and Evans, 1986). Molecular cloning then identified five members of the kainate receptor family (GluR5, GluR6, GluR7, KA1, KA2; referred here according to IUPHAR nomenclature as GLUK5–7, GLUK1–2), which can exist in various homomeric and heteromeric assemblies (Bettler and Mulle, 1995). The subsequent development of kainate receptor knockout animals and selective pharmacological tools (Bleakman and Lodge, 1998) has enabled progress to be made in elucidating the functions of kainate receptors in the CNS (Chittajallu et al., 1999, Huettner, 2003, Lerma, 2003).
The activation of kainate receptors can regulate the level of synaptic inhibition in the hippocampus (Sloviter and Damiano, 1981, Westbrook and Lothman, 1983, Fisher and Alger, 1984, Kehl et al., 1984), possibly via a direct action on evoked GABAergic transmission (Davies and Collingridge, 1989, Clarke et al., 1997, Rodríguez-Moreno et al., 1997). However, the extent to which this represents a distinct effect in the vicinity of presynaptic terminals or arises as an indirect consequence of the increase in interneurone excitability is controversial (Cossart et al., 1998, Frerking et al., 1998, Bureau et al., 1999, Frerking et al., 1999, Rodríguez-Moreno et al., 2000).
In a previous work, we characterised an agonist (ATPA) and antagonist (LY294486) selective for GLUK5 receptors and used these, together with kainate, to identify a role of GLUK5-containing kainate receptors in the regulation of monosynaptically evoked GABAergic synaptic transmission in area CA1 of the hippocampus (Clarke et al., 1997). Although our experiments suggested that the effects of ATPA were directly on GABAergic neurones, it was subsequently proposed that kainate receptor activation leads to depression of inhibition indirectly; the hypothesis was that excitation of interneurones leads to GABA release which acts on GABAA receptors to shunt IPSPs and on GABAB receptors to cause inhibition of GABA release via presynaptic GABAB receptors (Frerking et al., 1999).
One purpose of the present work was to re-investigate this possibility. We find no evidence for an indirect effect via GABA release. In addition, we determined the sensitivity of the effects of ATPA to the more selective GLUK5 kainate receptor antagonist LY382884 (Bortolotto et al., 1999). Our results suggest that this antagonist displays a differential sensitivity at antagonising the GLUK5 containing kainate receptors that regulate GABA and glutamate release.
Section snippets
Materials and methods
Wistar rats in the age range 10–16 weeks were either anaesthetised with halothane (3.5%) and decapitated or killed according to schedule 1, in accordance with UK Home Office legislation. The brain was removed rapidly and placed in ice-chilled, oxygenated artificial cerebrospinal fluid (aCSF) comprising of (in mM): NaCl 124, KCl 3, NaHCO3 26, CaCl2 2, MgSO4 1, d-glucose 10, NaH2PO4 1.25 saturated with 95% O2, 5% CO2. Parasaggital slices (400 μm thick) containing the hippocampal region were
Effects of ATPA on intracellular properties and evoked excitatory transmission
Initially we examined the effects of ATPA on evoked EPSPs and passive membrane properties (Fig. 1). At a concentration of 3 μM, ATPA caused a hyperpolarisation followed by a slower repolarisation to a level close to the initial baseline membrane potential, with an associated decrease in input resistance. EPSP amplitude was depressed by 42±9% (p<0.05), whilst input resistance was reduced by 8±1% (n=3; Fig. 1A). At a concentration of 10 μM, ATPA caused a larger hyperpolarisation (ca. 3–4 mV), and
Discussion
The purpose of the present study was to characterise in more detail the effects of ATPA on monosynaptically evoked GABAergic synaptic transmission in area CA1 of the adult rat hippocampus. Although ATPA can activate AMPARs, the use of GYKI53655 restricted its actions to kainate receptors; this was confirmed by the lack of the effects of AMPA on monosynaptically evoked IPSPs. GYKI53655 eliminated the depolarising action of ATPA, demonstrating that this was due to the activation of AMPA
Acknowledgements
This work has been supported by the MRC.
References (37)
- et al.
The LTP program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events
Journal of Neuroscience Methods
(2001) - et al.
AMPA and kainate receptors
Neuropharmacology
(1995) - et al.
Kainate receptors: subunits, synaptic localisation and function
Trends in Pharmacological Sciences
(1999) - et al.
Characterisation of the effects of ATPA, a GLUK5 receptor selective agonist, on excitatory synaptic transmission in area CA1 of rat hippocampal slices
Neuropharmacology
(2002) - et al.
CGP 55845A: a potent antagonist of GABAB receptors in the CA1 region of rat hippocampus
Neuropharmacology
(1993) Kainate receptors and synaptic transmission
Progress in Neurobiology
(2003)- et al.
A Kainate receptor increases the efficacy of GABAergic synapses
Neuron
(2001) - et al.
Effects of folic and kainic acids on synaptic responses of hippocampal neurones
Neuroscience
(1984) - et al.
A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP
Neuron
(2001) - et al.
The antagonism of amino acid-induced excitation of spinal neurones in the cat
Brain Research
(1979)
Subunit composition of kainate receptors in hippocampal interneurons
Neuron
Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus
Neuron
On the relationship between kainic acid-induced epileptiform activity and hippocampal neuronal damage
Neuropharmacology
Presynaptic inhibition in the hippocampus
Trends in Neurosciences
The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus
Neuropharmacology
Cellular and synaptic basis of kainic acid-induced hippocampal epileptiform activity
Brain Research
The primary afferent depolarising action of kainate in the rat
British Journal of Pharmacology
Neuropharmacology of AMPA and kainate receptors
Neuropharmacology
Cited by (19)
Domoic acid suppresses hyperexcitation in the network due to activation of kainate receptors of GABAergic neurons
2019, Archives of Biochemistry and BiophysicsPresynaptic facilitation of glutamate release in the basolateral amygdala: A mechanism for the anxiogenic and seizurogenic function of GluK1 receptors
2012, NeuroscienceCitation Excerpt :Signals were digitized using the pClamp10.2 software (Molecular Devices, Union City, CA), analyzed using Clampfit 10.2, and final presentation was prepared using Origin (OriginLab Corporation, Northampton, MA). Drugs used were as follows: bicuculline methiodide, a GABAA receptor antagonist, and tetrodotoxin (TTX), a sodium channel blocker, both from Sigma–Aldrich (St. Louis, MO); D-AP5, an N-methyl-D-aspartate (NMDA) receptor antagonist, SCH50911, a GABAB receptor antagonist, ATPA, a selective GluK1R agonist (Clarke et al., 1997; Clarke and Collingridge, 2002, 2004; Jane et al., 2009), and (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4-dione (UBP302), a selective GluK1R antagonist, with similar affinity for homomeric and heteromeric GluK1 kainate receptors (More et al., 2004), were all obtained from Tocris (Ellisville, MO). Male, Sprague–Dawley rats (200–220 g) were individually housed in an environmentally controlled room (20–23 °C, 12-h-light/12-h-dark cycle, lights on 06:00 pm), with food and water available ad libitum.
3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: Molecular modeling and pharmacological studies
2012, European Journal of Medicinal ChemistryDeletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference
2010, Neuroscience Letters