Elsevier

Neuropharmacology

Volume 53, Issue 1, July 2007, Pages 37-47
Neuropharmacology

Pre- and postsynaptic effects of kainate on layer II/III pyramidal cells in rat neocortex

https://doi.org/10.1016/j.neuropharm.2007.04.008Get rights and content

Abstract

Kainate receptors mediate both direct excitatory and indirect modulatory actions in the CNS. We report here that kainate has both pre- and postsynaptic actions in layer II/III pyramidal neurons of rat prefrontal cortex. Application of low concentration of kainate (50–500 nM) increased the amplitude of evoked excitatory postsynaptic currents (EPSCs) whereas higher concentrations (3 μM) caused a decrease. The frequency of spontaneous and miniature (action potential-independent) EPSCs was increased by low concentrations of kainate without affecting their amplitudes, suggesting a presynaptic mechanism of action. The facilitatory and inhibitory effects of kainate were mimicked by the GluR5 subunit selective agonist ATPA. In addition to decreasing EPSC amplitudes, high concentrations of kainate and ATPA induced an inward current which was not blocked by AMPA- or NMDA-receptor antagonists GYKI52466 and D-APV, respectively. The inward currents were blocked by the AMPA/KA receptor antagonist CNQX, indicating the presence of postsynaptic kainate receptors. Single shock stimulation in the presence of GYKI52466 and D-APV evoked an EPSC which was blocked by CNQX. The GluR5 antagonist LY382884 changed paired-pulse facilitation to paired pulse depression, indicating that synaptically released glutamate can activate presynaptic kainate receptors. These results suggest that kainate receptors containing GluR5 subunits play a major role in glutamatergic transmission in rat neocortex, having both presynaptic modulatory and direct postsynaptic excitatory actions.

Introduction

Early studies comparing the distribution of mRNAs encoding for five different kainate receptor subunits (GluR5–7, KA-1, and KA-2) found that these subunits are all abundantly expressed in neocortex (Wisden and Seeburg, 1993). GluR5–7 are known to form functional homomeric glutamate receptors (Hollmann and Heinemann, 1994, Bettler and Mulle, 1995, Schiffer et al., 1997) whereas KA1 and KA2 do not (Werner et al., 1991, Herb et al., 1992). KA1 and KA2 can co-assemble with GluR5–7 to make channels with unique functional properties (Hollmann and Heinemann, 1994, Chittajallu et al., 1999). The existence of splice variants and mRNA editing suggests additional complexity in kainate receptor subunit composition (Chittajallu et al., 1999). The exact subunit stoichiometry of native kainate receptors in neocortex, or elsewhere, has not been determined. In addition, the role of individual subunits in kainate receptor-mediated responses in neocortex has not been established.

Advances in the study of kainate receptors and their role in synaptic transmission occurred when agents enabling pharmacological isolation of kainate-mediated responses became available (Paternain et al., 1995, Wilding and Huettner, 1995). Application of selective antagonists of N-methyl-d-aspartate (NMDA) (e.g., D-APV) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA) (e.g., GYKI52466 or SYM 2206) receptors allowed identification of kainate receptor-mediated responses. Pharmacological tools also exist to delineate effects mediated by kainate receptors containing GluR5 subunits. (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl) proprionic acid (ATPA), at low concentrations, is a selective GluR5 agonist (Clarke et al., 1997) and the GluR5 subunit is selectively blocked by (3S,4aR,6S,8aR)-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) (Bortolotto et al., 1999).

EPSCs mediated by postsynaptic kainate receptors have been described in pyramidal and fast-spiking cells in layers II/III and V of rat motor cortex (Ali, 2003). Kainate EPSCs have also been observed in neonatal layer IV neurons where they exhibit very slow kinetics (Kidd and Isaac, 2001). Kainate receptors are located along the entire somatodendritic compartment of layer V pyramidal neurons, mediating synaptic and extrasynaptic responses (Eder et al., 2003). Presynaptic kainate receptors located on synaptic terminals of presynaptic fast-spiking interneurons decrease GABA release onto layer V pyramidal cells (Ali et al., 2001). Information about pre- and postsynaptic kainate receptors on layer II/III pyramidal cells and their subunit composition is lacking.

Ionotropic glutamate receptors have traditionally been assumed to be located postsynaptically whereas metabotropic glutamate receptors are found both pre- and postsynaptically. This view has recently been undergoing revision since ionotropic kainate receptors are known to be located presynaptically in several brain regions including amygdala (Li et al., 2001), cerebellum (Delaney and Jahr, 2002), hippocampus (Vignes et al., 1998, Schmitz et al., 2001) and substantia nigra pars compacta (Nakamura et al., 2003) where they can either facilitate or depress synaptic transmission. In developing neocortex, high frequency stimulation or application of kainate receptor agonists produces a significant EPSC depression via presynaptic kainate receptors (Kidd et al., 2002). Glutamate release from isolated cerebral cortex nerve terminals (synaptosomes), evoked by 4-aminopyridine, is enhanced by presynaptic kainate receptors (Perkinton and Sihra, 1999), indicating that facilitatory autoreceptors are also present in neocortex. In the present study, we have examined the role of pre- and postsynaptic kainate receptors in regulating excitation of layer II/III pyramidal cells in rat neocortex. Our results indicate that kainate receptors containing GluR5 subunits tonically facilitate glutamate release and underlie kainate mediated EPSCs.

Section snippets

Slice preparation

Neocortical slices were prepared from Sprague–Dawley rats (17–24 days old). Animals were handled and housed according to the guidelines from the NIH Committee on Laboratory Animal Resources. All experimental protocols were approved by the University of Alabama Institutional Animal Care and Use Committee. Every effort was made to minimize pain and discomfort. Rats were anesthetized with ketamine (100 mg/kg) and decapitated. The brain was removed quickly and placed in ice-cold saline, which

Dose-dependent bi-directional effects of kainate on evoked EPSCs

In order to investigate the role of kainate receptors in regulating synaptic responses in neocortex, whole-cell voltage-clamp recordings were obtained from pyramidal cells in layer II/III. Synaptic responses were elicited by intracortical stimulation 150–200 μm below the recording pipette. In the presence of BIC and at a holding potential of −70 mV, small amplitude, presumably AMPA-mediated, EPSCs were evoked with weak stimulation. A typical example of such an EPSC is shown in Fig. 1A. Responses

Discussion

We demonstrated here that activation of kainate receptors produces dose-dependent biphasic effects on EPSCs in layer II/III neocortical pyramidal cells. An enhancement of evoked EPSC amplitudes and increases in the frequency of both spontaneous and miniature EPSCs were observed at low kainate concentrations. The increase in the frequency but not the amplitude of mEPSCs indicates that facilitation was via a presynaptic mechanism. EPSC depression and a postsynaptic current were seen at higher

Acknowledgements

This work was supported by NIH grant NS22373 and P30 NS47466.

References (63)

  • F.L. Kidd et al.

    A presynaptic kainate receptor is involved in regulating the dynamic properties of thalamocortical synapses during development

    Neuron

    (2002)
  • S.E. Lauri et al.

    A critical role of a facilitatory presynaptic kainate receptor in mossy fiber LTP

    Neuron

    (2001)
  • S.E. Lauri et al.

    A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus

    Neuron

    (2003)
  • A.V. Paternain et al.

    Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons

    Neuron

    (1995)
  • M.S. Perkinton et al.

    A high-affinity presynaptic kainate-type glutamate receptor facilitates glutamate exocytosis from cerebral cortex nerve terminals (synaptosomes)

    Neuroscience

    (1999)
  • A. Rodriguez-Moreno et al.

    Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus

    Neuron

    (1997)
  • H.H. Schiffer et al.

    Rat GluR7 and carboxy-terminal splice variant,GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate

    Neuron

    (1997)
  • M. Vignes et al.

    The GluR5 subtype of kainate receptor regulates excitatory synaptic transmission in areas CA1 and CA3 of the rat hippocampus

    Neuropharmacology

    (1998)
  • A.B. Ali et al.

    Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex

    J. Neurosci.

    (2001)
  • A.B. Ali

    Involvement of post-synaptic kainate receptors during synaptic transmission between unitary connections in rat neocortex

    Eur. J. Neurosci.

    (2003)
  • S. Bahn et al.

    Kainate receptor gene expression in the developing rat brain

    J. Neurosci.

    (1994)
  • A.E. Bandrowski et al.

    Baseline glutamate levels affect group I and II mGluRs in layer V pyramidal neurons of rat sensorimotor cortex

    J. Neurophysiol.

    (2003)
  • Z.A. Bortolotto et al.

    Kainate receptors are involved in synaptic plasticity

    Nature

    (1999)
  • Z.A. Bortolotto et al.

    Kainate receptors and the induction of mossy fibre long-term potentiation

    Philos. Trans. R. Soc. B Biol. Sci.

    (2003)
  • M.F.M. Braga et al.

    Bidirectional Modulation of GABA release by presynaptic glutamate receptor 5 kainate receptors in the basolateral amygdala

    J. Neurosci.

    (2003)
  • J. Breustedt et al.

    Assessing the role of GLUK5 and GLUK6 at hippocampal mossy fiber synapses

    J. Neurosci.

    (2004)
  • I. Bureau et al.

    Kainate receptor-mediated synaptic currents in cerebellar Golgi cells are not shaped by diffusion of glutamate

    Proc. Natl. Acad. Sci. U.S.A.

    (2000)
  • P.E. Castillo et al.

    Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons

    Nature

    (1997)
  • P. Cavelier et al.

    Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices

    J. Physiol. (Lond.)

    (2005)
  • R. Chittajallu et al.

    Regulation of glutamate release by presynaptic kainate receptors in the hippocampus

    Nature

    (1996)
  • V.R.J. Clarke et al.

    A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission

    Nature

    (1997)
  • Cited by (35)

    • Presynaptic kainate and NMDA receptors are implicated in the modulation of GABA release from cortical and hippocampal nerve terminals

      2011, Neurochemistry International
      Citation Excerpt :

      A system of ionotropic glutamate presynaptic receptors involves three receptor subtypes, NMDA, AMPA and kainate, which are coupled with cation-selective channels permeable for univalent cations, Na+ and K+, and have a different degree of permeability to Ca2+. Activation of presynaptic glutamate receptors can transiently change as excitatory as inhibitory neurotransmission, causing either suppression or enhancement of their efficacy (Chittajallu et al., 1996; Rodriguez-Moreno and Lerma, 1998; Cunha et al., 2000; Kullmann, 2001; Cossart et al., 2001; Belan and Kostyuk, 2002; Campbell et al., 2007). Such contrary responses to activation of glutamate receptors could be, at least in part, attributable to the occurrence of distinct subtypes of receptors that use different signaling pathways (Cossart et al., 2001; Braga et al., 2003; Cunha et al., 2004; Lerma, 2006).

    View all citing articles on Scopus
    View full text