Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit - PubMed (original) (raw)

Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit

Karri P Lamsa et al. Science. 2007.

Abstract

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-D-aspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian":Itis induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.

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Figures

Fig. 1

Fig. 1

Associative pairing precludes LTP in interneurons in the stratum oriens/alveus. (A) Left: Schematic illustrating in-phase high-frequency burst (HFB) stimulation of weak and strong alveus pathways (filled and open symbols, respectively). Sample traces (1 to 5) show action potentials evoked by pairing in one cell. Right: Baseline-normalized EPSP initial slopes (mean ± SEM). (B) Top: Averaged EPSPs recorded before (blue) and after (red) pairing in one cell, showing the interval used to measure the initial slope. Bottom: Baseline-normalized EPSP initial slopes (25 min after pairing) in the two pathways, plotted against one another. (C) Antiphase pairing of two weak pathways induced LTP in seven out of seven cells. Sample traces (left) are from one cell. (D) EPSPs before and after pairing and summary of results, plotted as in (B). (E) Burst stimulation of one pathway also induced LTP. AMPA/kainate receptors were blocked at the end of the experiment (NBQX), to verify that EPSP initial slopes were not contaminated by monosynaptic inhibition. (F) Effect of HFB stimulation of one pathway (weak 1), plotted as for (B) and (D). Traces (top) also show the effect of NBQX. Data in (C) (right) and (E) (right) are shown as the mean ± SEM. _V_m, membrane potential.

Fig. 2

Fig. 2

Postsynaptic membrane potential gates anti-Hebbian LTP induction. (A) LTP was evoked by pairing presynaptic stimulation with the hyperpolarizing but not the depolarizing phase of an imposed sinusoidal membrane potential oscillation. Left: Schematic and sample membrane potential traces during pairing in one cell (five sweeps superimposed for each pairing protocol). Right: Baseline-normalized EPSP initial slopes in eight cells showing LTP after anti-Hebbian pairing of HFB stimulation of one pathway with hyperpolarization. Subsequent Hebbian pairing of the other pathway with depolarization was ineffective. AMPA/kainate receptors were blocked at the end of the experiment (NBQX). Data are shown as the mean ± SEM. (B) Averaged EPSPs in one cell taken at the times indicated and after NBQX addition. Top: Anti-Hebbian pairing. Bottom: Hebbian pairing. (C) LTP was induced by pairing single stimuli at 5 Hz with hyperpolarization. Left: Sample traces during pairing. Right: Averages of all cells tested. Data are shown as the mean ± SEM. (D) Pairing with depolarization failed to induce LTP. Left: Sample traces during pairing. Right: Averages of all cells tested. Data are shown as the mean ± SEM. (E) Repatched interneurons recorded in whole-cell voltage-clamp mode show rectifying AMPARs and a negligible NMDAR-mediated component (GABA receptors blocked). Traces: Averaged EPSCs at +60 and −60 mV, showing the times at which the two components were measured. Bottom: current-voltage (I-V) relation of AMPAR-mediated EPSCs in six repatched interneurons (left). I-V relation for the NMDAR-mediated component, normalized by the AMPA EPSC at −60 mV (right).

Fig. 3

Fig. 3

Anti-Hebbian LTP occurs in interneurons with rectifying AMPARs in the feedback circuit. (A) High-frequency stimulation (HFS) paired with hyperpolarization evoked LTP in 25 out of 31 interneurons in the oriens/alveus [NMDARs blocked with 100 μM

d

,

l

-2-amino-5-phosphonovalerate (APV)]. Insets: Averaged EPSPs before and after LTP induction, and membrane potential during pairing, in one interneuron. Data are shown as the mean ± SEM. (B) Repatched interneurons recorded in whole-cell voltage-clamp mode revealed strongly rectifying synaptic AMPARs (rectification index < 0.3). Gray and open symbols show cells that did and did not exhibit LTP, respectively. Insets: Averaged EPSCs at −60 and +60 mV in one cell that showed anti-Hebbian LTP. (C) O-LM cells were the commonest identified interneuron type exhibiting anti-Hebbian LTP (left: schematic, with dendritic and axonal arborizations for one cell shown in red and blue, respectively). Three fast spiking perisomatic-projecting neurons were also identified, including a basket cell (right). Scale bar: 200 μm. Firing patterns in response to current injection (_I_c) are shown below. (D) Typical layer- and pathway-specific properties of EPSCs in experiments where NMDARs were not blocked (n, number of repatched interneurons). Interneurons were recorded in the stratum radiatum (1), stratum pyramidale (2), and stratum oriens/alveus (3). (E) Success rates for eliciting Hebbian or anti-Hebbian LTP at synapses made by axons illustrated in (D). (F) Anti-Hebbian LTP requires activation of AMPA/kainate receptors. HFS stimulation of one pathway (filled symbols) was paired with hyperpolarization in NBQX (5 μM) (inset). After wash-out, EPSPs in both pathways recovered at the same rate. Inset: Averaged EPSPs before pairing (blue) and after recovery (red) in the two pathways in one experiment. Data are shown as the mean ± SEM.

Fig. 4

Fig. 4

Intracellular polyamines determine the voltage dependence of anti-Hebbian LTP. (A) Postsynaptic depolarization prevents LTP induction. Data from cells recorded in perforated patch mode, showing LTP induced by pairing high-frequency stimulation (HFS) of one pathway with hyperpolarization (top, “anti-Hebbian”), and failure to induce LTP by pairing the other pathway with depolarization (bottom, “Hebbian”). NMDARs were blocked throughout. Data are the mean ± SEM. (B) In six other cells, the second pathway was subsequently paired with hyperpolarization, yielding anti-Hebbian LTP in all cases. Data are the mean ± SEM. (C) Baseline-normalized EPSP slopes plotted against one another 20 min after anti-Hebbian (left) and Hebbian (right) pairing. Insets: Sample membrane potential traces during pairing. (D) Anti-Hebbian LTP was first induced in one pathway (left, filled symbols). The interneuron was then repatched in whole-cell mode with a polyamine-free pipette solution. HFS delivered to the second pathway (right, open symbols) paired with postsynaptic depolarization (+20 mV) induced LTP. Top: Voltage (left) and current (middle, with seal resistance test artefacts) traces during pairing, and one O-LM cell identified among five interneurons in the sample (right; scale bar: 200 μm). (E) Intracellular spermine blocked LTP induction in the second pathway when paired with depolarization. Top: As in (D). (F) LTP was induced with intracellular spermine when paired with hyperpolarization (−90 mV). Top: As in (D) and (E). Data in (D), (E), and (F) (bottom panels) are shown as the mean ± SEM.

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