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