In hippocampal oriens interneurons anti-Hebbian long-term potentiation requires cholinergic signaling via α7 nicotinic acetylcholine receptors

Abstract

In the hippocampus, at excitatory synapses between principal cell and oriens/alveus (O/A) interneurons, a particular form of NMDA-independent long-term synaptic plasticity (LTP) has been described (Lamsa et al., 2007). This type of LTP occurs when presynaptic activation coincides with postsynaptic hyperpolarization. For this reason it has been named "anti-Hebbian" to distinguish from the classical Hebbian type of associative learning where presynaptic glutamate release coincides with postsynaptic depolarization. The different voltage dependency of LTP induction is thought to be mediated by calcium-permeable (CP) AMPA receptors that, due to polyamine-mediated rectification, favor calcium entry at hyperpolarized potentials. Here, we report that the induction of this form of LTP needs CP-α7 nicotinic acetylcholine receptors (nAChRs) that, like CP-AMPARs, exhibit a strong inward rectification because of polyamine block at depolarizing potentials. We found that high-frequency stimulation of afferent fibers elicits synaptic currents mediated by α7 nAChRs. Hence, LTP was prevented by α7 nAChR antagonists dihydro-β-erythroidine and methyllycaconitine (MLA) and was absent in α7(-/-) mice. In addition, in agreement with previous observations (Le Duigou and Kullmann, 2011), in a minority of O/A interneurons in MLA-treated hippocampal slices from WT animals and α7(-/-) mice, a form of LTP probably dependent on the activation of group I metabotropic glutamate receptors was observed. These data indicate that, in O/A interneurons, anti-Hebbian LTP critically depends on cholinergic signaling via α7 nAChR. This may influence network oscillations and information processing.

Figure 1.

Synaptic currents mediated by α7-nAChRs in O/A interneurons. A, nAChR-mediated EPSCs evoked in a O/A interneuron by repetitive stimulation of cholinergic fibers in the O/A border (100 Hz for 1 s) at −80 mV, at +30 mV. Note that synaptic currents could be detected at −80 mV but not at +30 mV due to their strong inward rectification. B, In another interneuron held at −80 mV, bath application of MLA (10 nm) blocked both the fast synaptic currents and the slow developing inward current. This effect was partially reversed 10 min after MLA was washed out. C, Peak EPSCs amplitude as a function of consecutive stimuli, before (white; n = 10) and during bath application of MLA (gray; n = 13). Vertical bars, SEM. D, Each column represents the charge transfer (pA*ms) obtained by summating respective areas underlying the first 5 consecutive EPSCs, recorded at −80 mV (white), at +30 mV (black) and at −80 mV in the presence of 10 nm MLA (gray).

Figure 2.

Anti-Hebbian LTP requires the activation of α7 nAChRs. A, B, Mean EPSP slope (obtained before and after pairing, arrows), normalized to pre-pairing values in the absence (A) and presence (B) of MLA 10 nm. In A, mean values were obtained by pooling together six cells monitored 10 min before and 30 min after HFS and 11 cells monitored 5 min before and 20 min after HFS. In B, mean values were obtained by pooling together 10 cells monitored 10 min before and 30 min after HFS and seven cells monitored 5 min before and 20 min after HFS. C, Cells exhibiting LTP in the presence of MLA (6 of 15; included in the summary graph in B). D, In the presence of MLA plus mGluR1/5 antagonists LY367385 and MPEP, the pairing protocol (arrow) failed to produce LTP (n = 15). Insets above the graphs represent EPSPs evoked before (left) and 30 min after (right) pairing. The inset in the middle represents EPSPs recorded during the HFS (bar) delivered to a O/A interneuron maintained hyperpolarized at −100 mV.

Figure 3.

α7^−/− mice express CP-AMPAR- but not α7 nAChR-mediated EPSCs. A, On the left, AMPA-mediated synaptic currents evoked in one O/A interneuron at −50 and at +50 mV, respectively (in hippocampal slices from WT animals) by stimulation of afferent fibers, in the presence of dl-AP5 (100 μm), gabazine (2.5 μm) and CGP 54656 (1 μm), showing strong inward rectification. On the right, I–V relationship of inwardly rectifying AMPA-mediated synaptic currents (n = 5 at +50 mV, n = 16 at all other potentials). Vertical bars represent the SEM. Note that at +50, the EPSC value is below that expected in the absence of rectification (dashed line). B, On the left example of AMPA-mediated EPSC in the absence (Control) and in the presence of philanthotoxin (2 μm; PhTx). On the right, individual and mean (±SEM, vertical bars) peak current amplitude values obtained in the absence (Con; open circles) or in the presence (closed circles) of PhTx. C, In WT animals, HFS of afferent fibers in the O/A border (50 Hz for 0.5 s, arrow) elicited in a O/A interneuron fast EPSCs. Note EPSC summation with consequent stimuli and a slowly developing inward current. D–F, As in A–C but from α7^−/− mice (the I–V relationship refers to 5 O/A interneurons at + 50 mV, and 16 at all other potentials). Note that in F, the HFS train (arrow) failed to elicit fast EPSCs or slow inward currents. In A, B and D, E, whole-cell recordings were performed with an intrapipette solution containing spermine (100 μm).

Figure 4.

Lack of anti-Hebbian LTP in α7^−/− mice. The pairing protocol (arrow) fails to induce LTP (n = 18). Insets represent EPSPs evoked before (left) and 30 min after (right) pairing.