G protein-activated inwardly rectifying potassium channels mediate depotentiation of long-term potentiation

Abstract

Excitatory synapses in the brain undergo activity-dependent changes in the strength of synaptic transmission. Such synaptic plasticity as exemplified by long-term potentiation (LTP) is considered a cellular correlate of learning and memory. The presence of G protein-activated inwardly rectifying K ؉ (GIRK) channels near excitatory synapses on dendritic spines suggests their possible involvement in synaptic plasticity. However, whether activitydependent regulation of GIRK channels affects excitatory synaptic plasticity is unknown. In a companion article we have reported activity-dependent regulation of GIRK channel density in cultured hippocampal neurons that requires activity of NMDA receptors (NMDAR) and protein phosphatase-1 (PP1) and takes place within 15 min. In this study, we performed whole-cell recordings of cultured hippocampal neurons and found that NMDAR activation increases basal GIRK current and GIRK channel activation mediated by adenosine A 1 receptors, but not GABAB receptors. Given the similar involvement of NMDARs, adenosine A1 receptors, and PP1 in depotentiation of LTP caused by low-frequency stimulation that immediately follows LTP-inducing high-frequency stimulation, we wondered whether NMDAR-induced increase in GIRK channel surface density and current may contribute to the molecular mechanisms underlying this specific depotentiation. Remarkably, GIRK2 null mutation or GIRK channel blockade abolishes depotentiation of LTP, demonstrating that GIRK channels are critical for depotentiation, one form of excitatory synaptic plasticity.adenosine receptor ͉ synaptic plasticity ͉ learning and memory ͉ protein phosphatase-1 ͉ extracellular field recording S ynaptic plasticity, the ability of neurons to modify the efficacy of synaptic transmission, is thought to provide the cellular basis for the profound influence of experience over information processing and storage in the brain (1, 2). For example, long-term potentiation (LTP), a long-lasting increase in excitatory synaptic strength after heightened synaptic activity (3), is believed to be the cellular correlate of learning and memory. Since the discovery of LTP in the hippocampus, a region known to be essential for learning and memory, LTP has been extensively characterized for the molecular mechanisms of its induction and expression that involves Ca 2ϩ influx through NMDA receptors (NMDARs), leading to a high level of intracellular Ca 2ϩ concentration, and activation of calcium/calmodulin-dependent kinase II (CaMKII) (3).Whether the excitatory synaptic activities generated by highfrequency stimulation (HFS) result in LTP depends on the pattern of synaptic inputs impinging on the postsynaptic CA1 neurons shortly afterward; LTP of field excitatory postsynaptic potential (fEPSP) of CA1 neurons fails to develop if the HFS of the Schaffer collateral nerve fibers is followed within minutes by low-frequency stimulation (LFS) (4, 5). This form of synaptic plasticity, called depotentiation, may be a mechanism to abort the LTP according to events that take...

NMDA receptor-dependent GABA B receptor internalization via CaMKII phosphorylation of serine 867 in GABA B1

“…This provides a means to keep individual glutamatergic synapses modifiable (38,39) and to spare them from inhibition through spillover of GABA. A previous study reported that NMDA receptor activation promotes surface expression of Kir3 channels in hippocampal neurons (40), which was paralleled with an increase in basal Kir3 currents and adenosine A 1 -mediated Kir3 currents (41). However, GABA B mediated Kir3 currents were not altered, in apparent conflict with an earlier report (42) and our own findings.…”

Degeneracy in hippocampal physiology and plasticity

“…A traditional method to study such plasticity mechanisms is to subject neuronal or synaptic structures to specific activity patterns towards understanding the rules for plasticity in specific components. Assessed through such protocols, distinct synapses show signature profiles of plasticity in terms of activity or cytosolic calcium patterns that result in such plasticity or what other forms of plasticity are concomitant with each other (Abbott and Nelson, 2000;Abbott and Regehr, 2004;Bi and Poo, 1998;Bliss and Collingridge, 1993;Bliss and Lomo, 1973;Chung et al, 2009a;Chung et al, 2009b;Cooper and Bear, 2012;Dittman et al, 2000;Dudek and Bear, 1992;Fortune and Rose, 2001;Frick et al, 2004;Jorntell and Hansel, 2006;Lin et al, 2008;Losonczy et al, 2008;Lujan et al, 2009;Magee and Johnston, 1997;Markram et al, 1997;Johnston, 2007, 2008;Shah et al, 2010;Sjostrom et al, 2008). This implies plasticity profile homeostasis (Anirudhan and Narayanan, 2015;Mukunda and Narayanan, 2017), where synapses and neurons of the same subtype respond similarly to analogous afferent activity, thereby resulting in a subtype-dependent rule for synaptic or neuronal plasticity.…”

“…These studies show that plasticity induction is dependent on influx of calcium through NMDA receptors (Christie et al, 1996;Collingridge and Bliss, 1987;Collingridge et al, 1983;Morris et al, 1986;Mulkey and Malenka, 1992;Nishiyama et al, 2000;Tsien et al, 1996;Wang et al, 2003), voltage-gated calcium channels (Brager and Johnston, 2007;Christie et al, 1996;Christie et al, 1997;Johnston et al, 1992;Moosmang et al, 2005;Nicholson and Kullmann, 2017;Wang et al, 2003), store-operated calcium channels (Baba et al, 2003;Garcia-Alvarez et al, 2015;Majewski and Kuznicki, 2015;Majewski et al, 2016;Prakriya and Lewis, 2015) and receptors on the ER activated by metabotropic receptors on the plasma membrane (Huber et al, 2000;Nishiyama et al, 2000;Verkhratsky, 2002). Additionally, voltage-gated channels and their auxiliary subunits (Anirudhan and Narayanan, 2015;Brager et al, 2013;Chen et al, 2006;Chung et al, 2009a;Chung et al, 2009b;Johnston et al, 2003;Jung et al, 2008;Kim et al, 2007;Lin et al, 2008;Lujan et al, 2009;Malik and Johnston, 2017;Nolan et al, 2004;Sehgal et al, 2013;Shah et al, 2010;Watanabe et al, 2002) have also been shown to critically regulate th...…”

“…Specifically, induction of intrinsic plasticity requires influx of cytosolic calcium with different kinetics and strengths of calcium translating to distinct strengths and directions of intrinsic plasticity (Brager and Johnston, 2007;Fan et al, 2005;Huang et al, 2005;Sjostrom et al, 2008;Wang et al, 2003). The components that mediate calcium entry for synaptic plasticity also mediate calcium entry for non-synaptic plasticity, including NMDA receptors (Chung et al, 2009a;Chung et al, 2009b;Engert and Bonhoeffer, 1999;Fan et al, 2005;Frick et al, 2004;Huang et al, 2005;Lin et al, 2008;Losonczy et al, 2008;Matsuzaki et al, 2004;Nagerl et al, 2004;Narayanan and Johnston, 2007;Tonnesen et al, 2014;Wang et al, 2003), voltage-gated calcium channels (Chung et al, 2009a;Chung et al, 2009b;Lin et al, 2008;Wang et al, 2003) and receptors on the ER (Ashhad et al, 2015;Brager and Johnston, 2007;Brager et al, 2013;Clemens and Johnston, 2014;Kim et al, 2017;. This implies that the arguments placed about synergistic interactions between different calcium sources and about degeneracy in the induction of synaptic plasticity extends to the induction of non-synaptic plasticity as well (Fig.…”

“…Similar to the study of synaptic plasticity, specific activity protocols (most of which are similar, if not identical, to synaptic plasticity protocols) are employed to assess plasticity in other protein molecules and structural changes. Plasticity in voltage-gated ion channels and other neuronal components that result in changes to neuronal intrinsic properties have been dubbed as intrinsic plasticity, and is known to occur in the hippocampus with reference to most activity-dependent protocols employed for inducing synaptic plasticity (Brager and Johnston, 2007;Chung et al, 2009a;Chung et al, 2009b;Fan et al, 2005;Frick and Johnston, 2005;Frick et al, 2004;Johnston and Narayanan, 2008;Kim and Linden, 2007;Lin et al, 2008;Losonczy et al, 2008;Magee, 2000;Mozzachiodi and Byrne, 2010;Narayanan and Johnston, 2007Nelson and Turrigiano, 2008;Remy et al, 2010;Sjostrom et al, 2008;Spruston, 2008;Wang et al, 2003;Zhang and Linden, 2003). Although it is generally assumed that intrinsic plasticity refers only to global changes in intrinsic excitability, it is important to recognize that intrinsic plasticity encompasses all intrinsic properties that are mediated by neuronal constitutive components (Llinas, 1988;Marder, 2011;Marder et al, 1996;Marder and Goaillard, 2006), including neuronal spectral selectivity conferred by specific sets of ion channels Hutcheon and Yarom, 2000) and calcium wave propagation mediated by receptors on the endoplasmic reticulum (Ross, 2012).…”