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. 2009 Jan 13;106(2):635-40.
doi: 10.1073/pnas.0811685106. Epub 2008 Dec 31.

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

Hee Jung Chung  1 , Woo-Ping Ge, Xiang Qian, Ofer Wiser, Yuh Nung Jan, Lily Yeh Jan
Affiliations

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

Hee Jung Chung et al. Proc Natl Acad Sci U S A. .

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 activity-dependent 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 GABA(B) receptors. Given the similar involvement of NMDARs, adenosine A(1) 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
NMDAR activation increases basal GIRK current in cultured hippocampal neurons. (A) An example of action potential firing in a hippocampal neuron recorded before and after removal of APV. (B) An example of TP-sensitive basal GIRK current before and after removal of APV (10 min). Representative traces of whole-cell current (Middle) with (red) or without (black) 120 nM TP, were obtained when the membrane potential was stepped to −120 mV for 100 ms from the holding potential of −70 mV (Top). (Bottom) TP-sensitive current obtained by digital subtraction. (C) Representative basal GIRK current amplitude as a function of time. Whereas the current remained constant in size after control solution change (control; ○) to fresh bath solution containing APV, the basal GIRK current increased in amplitude after removal of APV to activate synaptic NMDAR (●). (D) Quantification of basal GIRK current density (pA/pF) recorded from the same neurons before and after removal of APV (n = 5; *, P < 0.05).
Fig. 2.
Fig. 2.
NMDAR activation increases GIRK current stimulated by adenosine A1 receptors but not GABAB receptors in cultured hippocampal neurons. (A) Sample traces of outward GIRK currents recorded at −50 mV from the same neuron in dissociated hippocampal culture before and 15 min after removal of APV. The GIRK current was induced by adenosine A1 receptor agonist, CPA (5 μM), adenosine (100 μM), and GABAB receptor agonist, baclofen (50 μM). (B) The outward GIRK currents (pA) induced by CPA, adenosine, and baclofen, with lines connecting the measurements of the currents recorded from the same neuron before and after removal of APV for 15 min. (C) Normalized outward GIRK current induced by CPA (n = 11), adenosine (n = 5), and baclofen (n = 11) before and after removal of APV. The agonist-induced current after removal of APV was normalized to that before removal of APV for each neuron. *, P < 0.05; ***, P < 0.001.
Fig. 3.
Fig. 3.
Involvement of NMDAR, PP1, and adenosine A1 receptor for both GIRK channel regulation in cultured hippocampal neurons and depotentitation of LTP in hippocampal slices. (A) In cultured hippocampal neurons, NMDAR activation increases GIRK surface expression by stimulating PP1-dependent dephosphorylation of the GIRK channel GIRK2 subunit, thereby increasing insertion of GIRK channels from recycling endosomes to plasma membrane (see ref. 9). NMDAR activation also increases GIRK current stimulated by adenosine A1 receptors but not GABAB receptors (Fig. 2). (B) LFS delivered within minutes of HFS diminishes the propensity for LTP of fEPSP induced by HFS, leading to depotentiation. Such LFS-induced depotentiation requires the activity of NMDARs, A1 receptors, and PP1 (4, 6).
Fig. 4.
Fig. 4.
GIRK2 null mutant mice failed to display depotentiation of LTP of fEPSP. (A and B) Example of LTP of fEPSP at the Schaffer collateral–CA1 synapses induced by HFS (100 Hz for 1 s, twice) in a hippocampal slice from the wild-type mice (+/+, black open circle, A) or GIRK2 knockout mice (−/−, red open circle, B). Sample field potential responses taken at the time points indicated as 1 and 2 are shown above. (C) Summary of LTP induced by HFS in hippocampal slices from wild-type mice (+/+, black open circle, n = 5 from 4 mice) and GIRK2 knockout mice (−/−, red open circle, n = 4 from 3 mice). (D) Example of depotentiation induced by LFS (2 Hz for 10 min applied within 1–2 min of HFS) in a hippocampal slice from the wild-type mice (+/+, black open circle). (E) No depotentiation was induced by LFS in a hippocampal slice from GIRK2 knockout mice (−/−, red open circle). The field potential recordings at the time points indicated as 1 and 2 are shown above in D and E. (F) Summary of LFS-induced depotentiation in the wild-type mice (+/+, black open circle, n = 11 from 8 mice) and the absence of LFS-induced depotentiation in GIRK2 knockout mice (−/−, red open circle, n = 6 from 3 mice). LTP persisted in hippocampal slices from GIRK2 null mutant mice but not wild-type mice even after HFS was followed by LFS. (Scale bars: 0.5 mV, 20 ms.)
Fig. 5.
Fig. 5.
GIRK channel activity is required for depotentiation of LTP. (A) LFS failed to induce depotentiation in a wild-type mouse hippocampal slice exposed to the A1 receptor antagonist DPCPX (DP, 100 nM). (B) LFS also failed to induce depotentiation in a wild-type mouse hippocampal slice treated with the GIRK channel blocker TP (50 nM). (C) Quantification of the extent of fEPSP potentiation after HFS that induced LTP in both wild-type and GIRK2 null mutant hippocampal slices (LTP) or HFS followed by LFS that resulted in depotentiation in wild-type hippocampal slices (Depotentiation). The fEPSP slope after stimulation is normalized with the fEPSP slope before stimulation to yield the %fEPSP slope. Comparison of hippocampal slices from wild-type (+/+, grey), GIRK2 knockout mutant (−/−, red), and the wild-type hippocampal slices treated with the GIRK channel blocker TP (+/+, 50 nM, n = 7 from 4 mice) or the A1 receptor antagonist DPCPX (+/+, 100 nM, n = 4 from 3 mice) reveals that depotentiation requires both A1 receptor and GIRK channel function. ***, P < 0.005; *, P < 0.05.
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