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Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression

Abstract

Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53−/− mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.

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Figure 1: IRSp53−/− mice display impaired social interaction in three-chamber and direct interaction tests.
Figure 2: IRSp53−/− mice exhibit reduced ultrasonic vocalization and hyperactivity.
Figure 3: The NMDAR antagonist memantine and MPEP, a negative allosteric modulator of mGluR5, rescues social interaction in IRSp53−/− mice.
Figure 4: IRSp53−/− SC-CA1 hippocampal synapses exhibit reduced LTD of NMDAR EPSCs but normal LTD of AMPAR EPSCs and mGluR-dependent LTD.
Figure 5: The IRSp53−/− hippocampus exhibits stabilized F-actin and suppressed basal cofilin activity.
Figure 6: Memantine restores LTD of NMDARs and MPEP restores NMDAR function at IRSp53−/− hippocampal synapses.
Figure 7: IRSp53−/− mPFC neurons show reduced apical dendrite complexity, mEPSC frequency and amplitude, and excitatory synapse number.
Figure 8: Memantine restores neuronal firing in the IRSp53−/− mPFC and induces a difference in excitatory firing between WT and IRSp53−/− hippocampi.

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Acknowledgements

This study was supported by the National Research Foundation of Korea (to D.K., 2012-0008795; to Y.C.B., 2012-0009328) and the Institute for Basic Science (IBS-R002-D1 to E.K. and IBS-R002-G1 to M.W.J.).

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Authors

Contributions

W.C., Haram Park, Hanwool Park, Y.C., D.L. and M.-H.K. conducted electrophysiological experiments. S.Y.C. conducted neuron culture, immunoblot and behavior experiments. E.L., J.W.L., S.L. and I.R. conducted in vivo recording experiments. J.K., R.K. and J.C. conducted mouse behavior experiments. S.-G.P. conducted ultrasonic vocalization experiments. Y.S.C. conducted electron microscopy experiments. M.W.J., D.K., Y.C.B. and E.K. supervised the experiments and wrote the manuscript.

Corresponding author

Correspondence to Eunjoon Kim.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 IRSp53−/− mice display normal olfactory function in the buried food test and normal repetitive behavior.

(a) Time taken for mice to find buried food and begin to dig was measured. (SEM, n = 10, ns, not significant, two-sided Student's t-test). (b) WT and IRSp53−/− mice spend similar amounts of time in grooming in home cages without bedding. (SEM, n = 10, ns, not significant, two-sided Student's t-test). (c) IRSp53−/− mice show normal total time spent in grooming in a novel and small chamber without bedding, which was used to suppress other activities such as space exploration. (SEM, n = 13, ns, not significant, two-sided Student's t-test). (d) IRSp53−/− mice show normal marble burying behavior comparable to WT mice. (SEM, n = 6, ns, not significant, two-sided Student's t-test). (e) IRSp53−/− mice show digging behavior comparable to WT mice. (SEM, n = 7, ns, not significant, two-sided Student's t-test). (f-i) In automated 48-hr monitoring of movements, which uses weight displacement, IRSp53−/− mice show normal levels of grooming, rearing, and climbing, but did show enhanced locomotion. (SEM, n = 3, **P < 0.01, ns, not significant, two-sided Student's t-test).

Supplementary Figure 2 Heterozygous IRSp53+/− mice show normal social interaction, locomotor activity, and repetitive behavior.

(a and b) IRSp53+/− mice show normal social interaction and social novelty recognition in the three chamber test, as shown by the social preference index based on sniffing time (SEM, n = 6 for WT and 7 for HT, ns, not significant, two-sided Student's t-test). (c) IRSp53+/− mice show normal locomotor activity in the open field test. (SEM, n = 8 for WT and HT, Two-way ANOVA, repeated measures). (d) IRSp53+/− mice show normal levels of grooming in home cages. (SEM, n = 8 for WT and HT, ns, not significant, two-sided Student's t-test).

Supplementary Figure 3 Lower doses of memantine and MPEP do not rescue social interaction in IRSp53−/− mice.

(a and b) Representative heat maps of three-chambered social interactions in WT and KO mice treated with low-dose memantine and MPEP. (c-f) Quantification of the results in (a) and (b), as shown by the time spent in chamber (c), or sniffing the cage (e), with a stranger (S) vs. an object (O), or the social preference index for the chamber time (d), or sniffing time (f). KO mice treated with low-dose memantine (5 mg/kg; i.p.) or MPEP (10 mg/kg; i.p.) show no rescues in social interactions. Note that there is a tendency towards rescue for low dose memantine. (SEM, n = 10 for WT saline, 8 for WT memantine, 10 for WT MPEP, 9 for KO saline, 8 for KO memantine, and 11 for KO MPEP, *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, one way ANOVA).

Supplementary Figure 4 Memantine and MPEP do not normalize impaired ultrasonic vocalization and open-field hyperactivity in IRSp53−/− mice, but memantine rescues novel object recognition.

(a-d) Animals were treated with memantine (10 mg/kg; i.p.) or MPEP (30 mg/kg; i.p.) 30 min before the indicated behavioral measurements. (a and b) Ultrasonic vocalization (SEM, n = 8 for WT saline, 8 for WT memantine, 6 for WT MPEP, 8 for KO saline, 8 for KO MPEP, and 8 for KO memantine, **P < 0.01, ns, not significant, two-sided Student's t-test). (c) Hyperactivity (SEM, n = 8 for WT saline, 10 for WT memantine, 14 for WT MPEP, 9 for KO saline, 9 for KO memantine, and 14 for KO MPEP, *P < 0.05, **P < 0.01, two-sided Student's t-test). (d) Novel object recognition (SEM, n = 7 for WT saline and memantine, 6 for KO saline and memantine, **P < 0.01, ***P < 0.001, ns, not significant, two-sided Student's t-test).

Supplementary Figure 5 Full images of cropped blots presented in other figures.

(a) Full blots for Figure 5e, f. (b) Full blots for Figure 5g, h. (c) Full blots for Supplementary Figure 6a. (d) Full blots for Supplementary Figure 6d. (W; WT, K; KO, U; untreated control, N; NMDA treatment)

Supplementary Figure 6 Normal levels of paired-pulse ratio and NMDA/AMPA ratio of evoked EPSCs at IRSp53−/− mPFC synapses.

(a) Normal paired-pulse ratio in the IRSp53−/− mice. Representative current traces are shown. (SEM, n = 7 cells, 6 mice for WT and 7 cells from 5 mice for KO, Two-way ANOVA, repeated measures). (b) Normal NMDA/AMPA amplitude ratio of evoked EPSCs in the IRSp53−/− mice. Representative current traces are shown. The grey block inside the representative trace indicates 50 msec after stimulus. (SEM, n = 10 cells, 9 mice for WT and 11 cells from 9 mice for KO, ns, not significant, two-sided Student's t-test).

Supplementary Figure 7 Normal levels of total and phosphorylated cofilin in the IRSp53−/− mPFC and whole brain.

(a-c) mPFC, (d-f) whole brain (SEM, n = 6 for WT, KO cofilin/p-cofilin in mPFC, and n = 4 for WT, KO cofilin/p-cofilin in whole brain, ns, not significant, two-sided Student's t-test).

Supplementary Figure 8 Normal miniature inhibitory postsynaptic currents (mIPSCs) in the IRSp53−/− mPFC and hippocampus.

(a and d) Examples of mIPSCs from WT and KO layer II/III pyramidal neurons in the prelimbic region of the mPFC (a) and in the CA1 pyramidal neurons of the hippocampus (d). (b, c, e, and f) Quantification of mIPSC frequencies and amplitudes. (SEM, n = 15 cells, 4 mice for WT and KO mPFC; 14 cells, 4 mice for WT hippocampus; 13 cells, 4 mice for KO hippocampus, ns, not significant, two-sided Student's t-test).

Supplementary Figure 9 Memantine does not rescue mEPSCs in the IRSp53−/− mPFC.

(a) Examples of mEPSCs. WT and IRSp53−/− mPFC slices in the presence or absence of memantine (1 μM) were measured of mEPSCs in layer II/III pyramidal neurons. (b and c) Quantification of the results in (a), as shown by the frequency (b) and amplitude (c) of mEPSCs. (SEM, n = 15 for WT saline, n = 11 for WT memantine, n = 14 for KO saline, n = 13 for KO memantine, * P < 0.05, ** P < 0.01, ns, not significant, two-sided Student's t-test).

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Chung, W., Choi, S., Lee, E. et al. Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. Nat Neurosci 18, 435–443 (2015). https://doi.org/10.1038/nn.3927

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