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Comparative Study
. 2003 Dec 15;553(Pt 3):843-56.
doi: 10.1113/jphysiol.2003.053637. Epub 2003 Oct 10.

A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A

Vidar Jensen  1 , Katharina M M Kaiser, Thilo Borchardt, Giselind Adelmann, Andrei Rozov, Nail Burnashev, Christian Brix, Michael Frotscher, Per Andersen, Øivind Hvalby, Bert Sakmann, Peter H Seeburg, Rolf Sprengel
Affiliations
Comparative Study

A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A

Vidar Jensen et al. J Physiol. .

Abstract

In adult mice, long-term potentiation (LTP) of synaptic transmission at CA3-to-CA1 synapses induced by tetanic stimulation requires L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors containing GluR-A subunits. Here, we report a GluR-A-independent form of LTP, which is comparable in size to LTP in wild-type mice at postnatal day 14 (P14) but diminishes between P14 and P42 in brain slices of GluR-A-deficient mice. The GluR-A-independent form of LTP is sensitive to D(-)-2-amino-5-phosphonopentanoic acid (D-AP5), but lacks short-term potentiation (STP) and can also be observed in the pairing induction protocol. As judged by unaltered paired-pulse facilitation, this LTP form is postsynaptically expressed despite depleted extrasynaptic AMPA receptor pools with reduced levels of GluR-B, which accumulates in somata and synapses of CA1 pyramidal neurons in GluR-A-deficient mice. Our results show that in the developing hippocampus synaptic plasticity can be expressed by AMPA receptors lacking the GluR-A subunit.

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Figures

Figure 1
Figure 1. Disappearance of tetanization-induced field LTP between P14 and P42 in GluR-A-deficient mice
A, normalized extracellular field EPSP (fEPSP) slopes evoked at CA3-to-CA1 synapses in brain slices of wild-type (left) and GluR-A−/− mice (right) of the tetanized (filled circles) and non-tetanized control (open circles) pathway from 10 min before to 50 min after tetanic stimulation are displayed for mice at postnatal day 14 (P14), P28, P35 and P42. The insets show the means of six consecutive synaptic responses in the tetanized pathway before and 40 min after tetanization (grey and black traces, respectively) superimposed at different ages. B, mean LTP values, given as normalized extracellular fEPSP slopes, obtained 40–45 min after tetanization (broad grey columns) in wild-type and GluR-A−/− mice as a function of age. The thin open columns give the corresponding values for the non-tetanized control pathway. Vertical bars: s.e.m. Asterisks indicate degree of significance between LTP values in the tetanized and control pathways (two-tailed paired t test; *P = 0.02, **P < 0.002; N.S.: not significant). C, normalized extracellular fEPSP slopes evoked at CA3-to-CA1 synapses in brain slices of GluR-A−/− at P14 in the tetanized (filled circles) and non-tetanized control (open circles) pathway from 10 min before to 50 min after tetanic stimulation in the presence of 50 μmd-AP5. The inset shows the means of six consecutive synaptic responses before and 40 min after tetanization (grey and black traces, respectively) in the tetanized pathway. For A and C, only the last 10 min of a > 15 min stable baseline are shown. Vertical bars: s.e.m., arrows: time points of tetanic stimulation. Numbers of mice, see Table 1. D, paired-pulses prior to and 60 min after LTP induction (grey and black traces, respectively) in slices from wild-type (left) and GluR-A−/− mice (right) at P14 (see Methods and Table 1B).
Figure 2
Figure 2. Changes of pairing-induced cellular LTP during development
A, normalized EPSC amplitudes evoked at CA3-to-CA1 synapses in brain slices of wild-type (left) and GluR-A−/− mice (right) in the paired (filled circles) and unpaired pathways (open circles) from 10 min before to 60 min after pairing at P14 and P42. Cellular LTP was evoked by pairing low-frequency presynaptic stimulation (0.67 Hz) with postsynaptic depolarization to 0 mV for 3 min indicated by the two arrows. The insets show the means of five consecutive synaptic responses in the paired pathway before and 40 min after pairing (grey and black traces, respectively) superimposed at different ages. Vertical bars: s.e.m.; number of mice see Table 1C. B, mean LTP values, given as normalized EPSC amplitudes, averaged from recordings from 45 to 50 min after pairing (broad grey columns) in wild-type and GluR-A−/− mice as a function of age. The thin open columns give the corresponding values for unpaired control pathways. Vertical bars: s.e.m. Asterisks indicate degree of significance between LTP values in the paired and control pathways (two-tailed paired t test; *P = 0.01, *P < 0.001). C, normalized EPSC amplitudes evoked at CA3-to-CA1 synapses in brain slices of GluR-A−/− mice in the paired pathways from 10 min before to 20 min after pairing in the absence (filled circles) and presence (open circles) of 100 μmd-AP5.
Figure 3
Figure 3. Developmental changes in synaptically evoked EPSCs and glutamate-evoked whole-soma currents
A, recordings of synaptically evoked AMPA and NMDA EPSCs at P14 and P42 from CA1 pyramidal cells in slices from wild-type (open circle) and GluR-A-deficient (filled circle) mice. Traces are averages of 50–100 sweeps. B, increase of postsynaptic AMPA receptor-mediated EPSCs of CA1 pyramidal cells measured at P14, P28 and P42 in wild-type mice (open circles; n = 12, 7 and 10, respectively; P = 0.001 for P14 versus P42) and developmentally unaffected AMPA receptor-mediated EPSCs in GluR-A-deficient mice at P14, P28 and P42 (filled circles; n = 8, 5 and 3; P = 0.63 for P14 versus P42). AMPA receptor-mediated EPSCs are normalized to NMDA receptor-mediated EPSCs (IA/IN). Vertical bars: s.e.m.C, recordings of glutamate-activated AMPA and NMDA receptor currents from nucleated patches from CA1 pyramidal cells of acute brain slices obtained from P14 and P42 wild-type (open circles) and GluR-A-deficient (filled circles) mice. Nucleated patches were exposed to 1 mm glutamate for 2 ms. IA = AMPA receptor-mediated current, IN = NMDA receptor-mediated current. Traces are averages of 5–10 sweeps. D, unchanged extrasynaptic AMPA receptor-mediated currents of CA1 pyramidal cells (IA) at P14, P28 and P42 in wild-type mice (open circles; n = 5, 7 and 5, respectively) and also unaffected, but low AMPA receptor-mediated currents in GluR-A-deficient mice (filled circles; n = 8 at all ages).
Figure 4
Figure 4. Developmental changes in AMPA receptor subunit distribution
GluR-A to -D subunit distribution in hippocampi of wild-type and GluR-A-deficient mice at P14 and P42. Sagittal vibratome brain sections were immunostained with specific antibodies directed against GluR-A, -B, -B/C and -D subunits. Micrograph pictures of the hippocampal subunit distribution visualized by diaminobenzidine (DAB)-labelled secondary antibodies are given (scale bar for 4 upper rows: 1 mm). In the bottom row higher magnification shows putative interneurons positive for the GluR-D subunit (arrows) in the CA1 region. (Scale bar for lower row: 0.13 mm).
Figure 5
Figure 5. Developmental changes in AMPA receptor subunit expression
Expression of ionotropic glutamate receptor subunits in hippocampi of wild-type (WT) and GluR-A-deficient (GluR-A−/−) mice from P2 to P180. Total hippocampal proteins were isolated, and for each sample 8 μg was loaded on a 7 % SDS-polyacrylamide gel. Separated proteins were transferred to nitrocellulose, and the glutamate receptor subunits were visualized by selective antibodies and monitored by autoradiography. For each subunit the 14 samples (7 time points for each genotype) were analysed in one gel run. The α-subunit of the Ca2+-calmodulin-dependent protein kinase ll (α-CaMKII) was used as a positive control and β-actin was used as a control for lane loading. The experiment was repeated with at least three sets of mice. One representative example for each subunit is given. In wild-type mice, the expression of all glutamate receptor subunits reached its maximum between P14 and P28. In GluR-A-deficient mice the expression maximum was delayed until P28. In the GluR-D panel a non-specific protein recognized by a CHEMICON anti-GluR-D antibody is indicated by an asterix. This protein shows a transient expression in the first postnatal days in hippocampi of wild-type and GluR-A-deficient mice and is also present in GluR-D ‘knockout’ mice (not shown).
Figure 6
Figure 6. Accumulation of the GluR-B subunits in somata and at synapses of GluR-A-deficient mice
A, immunofluorescence-labelled GluR-B (white signal) in hippocampus of wild-type and GluR-A-deficient mice indicating somatic accumulation of the GluR-B subunit in GluR-A-deficient mice. Scale bar: 1 mm. Insets display the approximate position of the confocal images of labelled GluR-B in the stratum pyramidale (Py) and radiatum (Ra) in the CA1 region. Pyramidal CA1 cell nuclei are black, without fluorescent signal. In GluR-A−/− mice cell somata and the most proximal part of the dendrite show strong fluorescent staining (right). In the stratum radiatum of wild-type mice the GluR-B-specific fluorescent signal is evenly distributed in tiny spots (arrows, less then 1 μm) all over the stratum radiatum. The overall fluorescence is high and cellular structures cannot be resolved. In GluR-A-deficient mice, total fluorescence in the stratum radiatum is weaker and the proximal part of dendrites can now be seen. The tiny GluR-B immunospots (arrows) are also present. They are sitting on the shafts of the dendrites and might represent large GluR-B-containing spine heads. Scale bar: 10 μm. B, example of an increased number of immunogold-labelled GluR-B-containing receptors at spine synapses (s) in the stratum radiatum of GluR-A-deficient (right) compared to wild-type mice (left). Scale bar: 0.1 μm. C, immunogold labelling for GluR-A at a spine synapse(s) in the stratum radiatum of the CA1 region in wild-type mice. Scale bar: 0.1 μm. B and C, graphs show the quantitative analysis of GluR-A- and GluR-B-containing AMPA receptors in CA1 synapses. The grey bars give the frequency of gold grains per synapse (I-gold part./synapse) detected for GluR-B and GluR-A, respectively, in wild-type (WT) and GluR-A-deficient (GluR-A−/−) mice. To account for possible background staining, synapses showing only one gold grain were counted as unlabelled. Experimental data were then fitted by Poisson distribution (lines) to estimate the total number of AMPA receptor-containing synapses (see Table 2).
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