Metabotropic-Mediated Kainate Receptor Regulation of IsAHP and Excitability in Pyramidal Cells

Abstract

Kainate receptors (KARs) on CA1 pyramidal cells make no detectable contribution to EPSCs. We report that these receptors have a metabotropic function, as shown previously for CA1 interneurons. Brief kainate exposure caused long-lasting inhibition of a postspike potassium current (I(sAHP)) in CA1 pyramidal cells. The pharmacological profile was independent of AMPA receptors or the GluR5 subunit, indicating a possible role for the GluR6 subunit. KAR inhibition of I(sAHP) did not require ionotropic action or network activity, but was blocked by the inhibitor of pertussis toxin-sensitive G proteins, N-ethylmaleimide (NEM), or the PKC inhibitor calphostin C. These data suggest how KARs, putatively containing GluR6, directly increase excitability of CA1 pyramidal cells and help explain the propensity for seizure activity following KAR activation.

KRIP6: A novel BTB/kelch protein regulating function of kainate receptors

“…Kainate receptors are widely expressed in the central nervous system (Wisden and Seeburg, 1993), where they can act pre-and post-synaptically. In the hippocampus, postsynaptic kainate receptors are thought to mediate excitatory transmission via an ionotropic action (Castillo et al, 1997;Cossart et al, 2002;Cossart et al, 1998) and to regulate excitability via a metabotropic function (Melyan et al, 2004;Melyan et al, 2002;Ruiz et al, 2005). Activation of presynaptic kainate receptors regulates glutamate and GABA release (Kullmann, 2001;Rodriguez-Moreno and Lerma, 1998) and modulates excitability in mature (Schmitz et al, 2000) and developing hippocampus.…”

A Novel Role for Protein Synthesis in Long-Term Neuronal Plasticity: Maintaining Reduced Postburst Afterhyperpolarization

“…Long-term reduction in the slow AHP can be also induced in CA1 pyramidal neurons by synaptically released glutamate, evoked by tetanic stimulation of the Schaffer collateral and commissural fibers (Melyan et al, 2002). Here, we show that such synaptic activation-induced postburst AHP reduction requires protein synthesis for its long-term maintenance.…”

“…Short-term reduction in the postburst AHP can be induced also in vitro, much like early LTP, by repetitive tetanic synaptic stimulation (Melyan et al, 2002). A similar effect is obtained by briefly exposing these neurons to kainate (Melyan et al, 2004).…”

“…Because of this technical constraint, the mechanism underlying postburst AHP reduction have been studied to date at two time windows. The first, during and up to 45 min after HFS application (Melyan et al, 2002(Melyan et al, , 2004, and the second, after 1 to several days after behavioral manipulations Zelcer et al, 2006). The combination of these two approaches leaves the time window of several hours after synaptic activation, when protein synthesis-dependent processes are expected to occur (Krug et al, 1984;Otani et al, 1989;Frey et al, 1993Frey et al, , 1988Nguyen et al, 1994), unexplored.…”

Developmental Biology of Neoplastic Growth

“…Kainate receptors play a variety of roles in the mammalian CNS (Lerma 2006 Schmitz et al 2000;Frerking et al 2001;Jiang et al 2001), modulate some forms of synaptic plasticity (Bortolotto et al 1999;Contractor et al 2001;Lauri et al 2001;Schmitz et al 2003), control neuronal excitability through inhibitory actions on intrinsic conductances (Melyan et al 2002(Melyan et al , 2004Fisahn et al 2005), and can contribute to temporal summation of postsynaptic depolarization in response to bursts of action potentials (Castillo et al 1997;Vignes and Collingridge 1997;Frerking and Ohliger-Frerking 2002;Jin et al 2006). Despite these widespread actions in neuronal function, inhibition of kainate receptors (or genetic ablation of one or more subunits) does not have the profound impact on brain activity observed upon inhibition of AMPA receptors (Mulle et al 1998(Mulle et al , 2000Simmons et al 1998;Smolders et al 2002;Contractor et al 2003;Alt et al 2007;Pinheiro et al 2007).…”