Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory

In the original publication of this paper, we reported that paired activation of the direct cortical and Schaffer collateral inputs to CA2 pyramidal neurons induced a form of long-term plasticity (input timing-dependent plasticity or ITDP) resulting from a ∂-opioid-receptor-mediated long-term depression of feedforward inhibition. We also found that infusion of the ∂-opioid receptor antagonist naltrindole into dorsal CA2 impaired social memory. We now write to correct one erroneous experimental result reported in Figure S8, panel A1, and to clarify the nature of a control group used for certain experiments.

In Figure S8A1, we reported that the ∂-opioid receptor agonist DPDPE did not alter inhibitory synaptic transmission onto CA3 pyramidal neurons in hippocampal slice experiments. However, after publication of our paper, it was brought to our attention that DPDPE does suppress inhibition in CA3. We have since repeated these experiments using a new batch of DPDPE (Catalog number 1431, Lot 12A, Tocris, Minneapolis) and confirmed that the agonist did, in fact, decrease inhibition in dorsal CA3a. Under voltage clamp, we now find that the inhibitory postsynaptic current (IPSC) in CA3a pyramidal neurons elicited by electrical stimulation in stratum radiatum was reduced to 50% ± 10% of its initial baseline level (revised Figure S8A1; n = 9, Wilcoxon test, p = 0.008), similar to the effect reported in CA2 (Piskorowski and Chevaleyre, 2013). We suspect that the previous aliquot of DPDPE we used may not have been active.

Based on this erroneous result, we argued that the behavioral effects of infusion of naltrindole into dorsal CA2 were unlikely to result from an action of the antagonist in neighboring dorsal CA3 to suppress ∂-opioid-receptor-dependent inhibitory plasticity in dorsal CA3. Given that we now agree that inhibitory synaptic transmission in dorsal CA3 is indeed suppressed by ∂-opioid receptor activation, we can no longer rule out this possibility. However, as recent findings show that ventral CA3, but not dorsal CA3, is important for social memory (Chiang et al., 2018), we believe that any action of naltrindole in dorsal CA3 is unlikely to account for its behavioral effects on social memory.

The second point concerns a clarification with certain control data. We wish to specify that we used the ITDP data shown in Figure 1E (time plot) and 1F (bar plot at −20 ms) as control data for three experiments performed under identical conditions shown in separate figures (control bar in Figure 2C, E-E pairing in Figure 4D, social novelty occlusion of ITDP in Figures 8E1 and 8E2). In all cases, the control group was treated identically to the experimental group apart from the given experimental manipulation. For the ITDP occlusion experiment, we added two extra cells to the control time plot in Figure 8E1. We had inadvertently omitted these two additional cells in the bar graph plot (Figure 8E2) and now include them in a revised Figure 8. Addition of these two extra data points does not alter our conclusions. We apologize for not specifying the repeated use of a single control group in our paper.

Figure 8. ∂-Opioid Receptor Blockade in CA2 Reduces Social Memory and Social Memory Occludes ITDP.

(A) Schematic of the direct interaction test for social memory.

(B) Interaction time of saline-injected (B1) and naltrindole-injected (B2) animals in trials 1 and 2 (symbols from individual animals) and superimposed mean ± SEM (B3).

(C) Percent reduction of interaction time from trial 1 to trial 2. Percent reduction in social interaction was calculated by taking the difference between social exploration time in trials 1 and 2 and then dividing by the social interaction time in trial 1, multiplied by 100%.

(D) Mini-Ruby infusion in the hippocampus and immunohistochemistry for RGS14.

(E) Exposure to social novelty occludes ITDP. (E1) Time course of mean ± SEM normalized SC-evoked PSP amplitude in CA2 pyramidal neurons obtained in whole-cell current clamp following ITDP induction. Slices were prepared from mice that either experienced a 2 min interaction with a novel juvenile male (social novelty; Occlusion group, n = 9 cells) or were continuously housed with littermates (social familiarity; Control group, n = 15 cells). Two additional control cells were included in this group compared to that in Figures 1E, 2C, and 4D. Note pronounced reduction in ITDP in response to social novelty (F = 2.9, p < 0.0001; ANOVA).

(E2) Amplitude of ITDP of PSPs evoked by stimulation of SC (filled circles) or EC (open squares) inputs to CA2 PNs in slices from indicated groups of animals. Symbols show data for single cells; bars show mean ± SEM. Both SC ITDP and EC ITDP Control groups now include two extra cells. SC ITDP magnitude in Occlusion group (n = 9) was significantly less than that in Control group (n = 21, p = 0.0003; Mann-Whitney test). See also Figure S8.