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Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network

Abstract

Hippocampal network activity is generated by a complex interplay between excitatory pyramidal cells and inhibitory interneurons. Although much is known about the molecular properties of excitatory synapses on pyramidal cells, comparatively little is known about excitatory synapses on interneurons. Here we show that conditional deletion of the postsynaptic cell adhesion molecule neuroligin-3 in parvalbumin interneurons causes a decrease in NMDA-receptor-mediated postsynaptic currents and an increase in presynaptic glutamate release probability by selectively impairing the inhibition of glutamate release by presynaptic Group III metabotropic glutamate receptors. As a result, the neuroligin-3 deletion altered network activity by reducing gamma oscillations and sharp wave ripples, changes associated with a decrease in extinction of contextual fear memories. These results demonstrate that neuroligin-3 specifies the properties of excitatory synapses on parvalbumin-containing interneurons by a retrograde trans-synaptic mechanism and suggest a molecular pathway whereby neuroligin-3 mutations contribute to neuropsychiatric disorders.

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Figure 1: NL3 deletion reduces NMDA receptor-mediated EPSCs in hippocampal PV interneurons.
Figure 2: Deletion of postsynaptic NL3 causes an increase in glutamate release probability at synapses on PV interneurons.
Figure 3: Increase in glutamate release caused by NL3 deletion at synapses on PV interneurons is due to loss of Group III mGluR-mediated presynaptic inhibition.
Figure 4: Changes in synaptic responses to repetitive stimulation as a result of NL3 deletion from PV interneurons.
Figure 5: Changes in hippocampal network activity as a result of NL3 deletion from PV interneurons.
Figure 6: Deletion of NL3 from CA1 PV interneurons compromises contextual fear extinction.

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Acknowledgements

We thank S. Maxeiner for sharing NL3fl mice, S. Fang and S. Atiyeh Afjei for help with stereotaxic injections, K. Lee for help with in vivo recording experiments and S. Botelho for help with biochemical assays. This work was supported by grants from NIH (P50MH086403 to R.C.M. and T.C.S.) and the Simons Foundation Autism Research Initiative Award 307762 (to T.C.S.).

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Authors

Contributions

J.S.P., T.C.S. and R.C.M. conceived the project, designed the experiments, and wrote and edited the manuscript. H.W. performed the in vivo electrophysiology experiments with input from C.H.H., and D.G. performed the immunohistochemistry experiments.

Corresponding author

Correspondence to Robert C Malenka.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Generation of NL3fl/PV-Cre mice and quantification of PV interneuron distribution in the hippocampus

a. Schematic representation of the mouse breeding strategy to generate NL3fl/PV-Cremice. b. Distribution of PV interneurons in the hippocampus. Representative coronal sections of the hippocampus from PV-Cre (top) and NL3fl/PV-Cre (bottom) mice showing PV-positive cells. c. Bar graph showing distribution of PV immunopositive cells in the hippocampus of PV-Cre (41 ± 3 cells/mm2, n = 3 mice) and NL3fl/PV-Cre mice (45 ± 3 cells/mm2, n = 3 mice).

Supplementary Figure 2 AAV injection at P21

a. Schematic representation of stereotaxic injection of AAV-hSyn-DIO-eGFP in P21 mice. b. Image of GFP expressing PV interneurons in the hippocampus of PV-Cre mice 10 days following AAV injection

Supplementary Figure 3 Inhibitory synaptic transmission onto PV interneurons is not changed by NL3 deletion.

a-b. (top) sample traces showing mIPSCs and (bottom) cumulative distribution plot for GABAA-R mediated mIPSC amplitude (a) and mIPSC frequency (b) from PV-Cre and NL3fl/PV-Cre cells showing no change due to NL3 deletion (p > 0.05, KS test for amplitude and frequency). Inset shows average mIPSC amplitude (PV-Cre, 22 ± 2 pA, n = 9 cells; NL3fl/PV-Cre, 21 ± 1 pA, n = 11 cells; p > 0.05) and mIPSC frequency (PV-Cre, 13 ± 2 Hz; NL3fl/PV-Cre 15 ± 2 Hz; p > 0.05).

Supplementary Figure 4 Summary plots of raw data showing the effects of various drugs on EPSCs and PPRs in PV interneurons.

a- before and after the application of CB1 receptor agonist WIN 55212-2 (5 μM) i, EPSCs; ii, PPRs in PV-Cre (black) and NL3fl/PV-Cre (orange) mice. b, same as in ‘a’ but for the application of CB1 receptor antagonist AM-251 (10 μM). c, same as in ‘a’ but for the application of Gr-III mGluR agonist L-AP4 (10 μM). d, same as in ‘a’ but for the application of Gr-III mGluR antagonist LY-341495 (1 μM). e, same as in ‘a’ but for the application of GABAB receptor agonist baclofen (10 μM). f, same as in ‘a’ but for the application of A1 receptor agonist N6-CPA (1 μM).

Supplementary Figure 5 GABAB-receptor- and A1-receptor-mediated presynaptic inhibition of excitatory synaptic transmission in PV interneurons are not affected by NL3 deletion

a-d, The depression of excitatory synaptic transmission in PV interneurons by the GABAB receptor agonist baclofen (10 μM) is not affected by NL3 deletion. Time course of normalized AMPAR EPSCs during application of baclofen (a) and sample EPSCs in response to paired pulse stimulation before and after baclofen application (b) in PV-Cre (before-black, after-blue) and NL3fl/PV-Cre (before-orange, after-green) neurons. Summary plot of normalized EPSC changes due to baclofen (c) and normalized PPR changes (d) in individual cells (PV-Cre, 0.4 ± 0.1, 1.3 ± 0.1, n = 4; NL3fl/PV-Cre, 0.4 ± 0.1, 1.3 ± 0.04, n = 6) e-h, Same as a-d but for the application of A1-R agonist N6-CPA (1 μM). Representative EPSCs (f) before and after N6-CPA for PV-Cre (before-black, after-blue) and NL3fl/PV-Cre (before-orange, after-green). Individual normalized EPSC (g) and PPR (h) changes caused after N6-CPA (PV-Cre, 0.3 ± 0.05, 1.1 ± 0.1, n = 6; NL3fl/PV-Cre, 0.3 ± 0.03, 1.0 ± 0.02, n = 4).

Supplementary Figure 6 Frequency-dependent attenuation of EPSCs in PV interneurons in PV-Cre and NL3fl/PV-Cre mice.

a-b, EPSC amplitudes from individual cells in response to stimulation trains at increasing frequencies. Responses in PV-Cre (black) and NL3fl/PV-Cre (orange) cells for 2 Hz, 5 Hz, 10 Hz and 20 Hz stimulation (a) and for 30 Hz, 50 Hz, 100 Hz, and 200 Hz stimulation (b). c, Logarithmic graph showing the summary data from Fig. 4a, b, presented as mean ± SEM of synaptic summation (of EPSCs) as a function of the stimulation frequency (2-200 Hz) for stimuli 1-10 (left) and 10-20 (right). NL3fl/PV-Cre cells show a low pass filtering in the frequency dependent summation of EPSCs from 30 Hz upwards.

Supplementary Figure 7 In vivo hippocampal CA1 LFPs show differences between PV-Cre and NL3fl/PV-Cre mice

a, Representative LFP traces (from left to right: unfiltered, 3-12 Hz band pass filtered, 35-85 Hz band pass filtered and 100-250 Hz band pass filtered) from the 4 recording channels from an individual PV-Cre mouse. b, Ratio of gamma normalized to theta is reduced in NL3fl/PV-Cre mice (PV-Cre, 0.19 ± 0.03, n = 5; NL3fl/PV-Cre 0.06 ± 0.01, n = 4; * p < 0.05). c, Combined normalized average of all captured, peak aligned SWRs from PV-Cre (black, n = 182) and NL3fl/PV-Cre (orange, n = 352).

Supplementary Figure 8 Virally injected DIO-NL3-Venus infects the majority of PV cells in the hippocampus.

a, Images of sections from AAV injected hippocampus from a NL3fl/PV-Cre mice showing colocalization of NL3-Venus (green) and anti-PV antibody (red). b, high resolution images from a section stained for PV (top), GFP (middle) and their colocalization (bottom, yellow). c, 86 ± 4% of PV-positive cells show AAV infection (n = 2 mice).

Supplementary Figure 9 Rescue of synaptic changes in NL3fl/PV-Cre cells by selective re-expression of NL3.

a, Representative traces of AMPAR EPSCs recorded at -60 mV and dual component EPSC at +40 mV (left). NMDAR/AMPAR ratio (right) is rescued by expression of NL3 in NL3fl/PV-Cre cells (NL3fl/PV-Cre+Rescue, 0.17 ± 0.02, n = 8 cells; p > 0.1 vs PV-Cre, *p < 0.05 vs NL3fl/PV-Cre). (PV-Cre and NL3fl/PV-Cre data from Fig. 1g.) b, Representative average traces (left) and summary graph (right) show rescue of paired-pulse ratios comparable to PV-Cre cells in NL3fl/PV-Cre+Rescue cells at inter-stimulus intervals of 20, 50, 100 and 200 ms (PV-Cre, 2.5 ± 0.1, 2.2 ± 0.1, 1.6 ± 0.1, 1.4 ± 0.1, n = 11 cells; NL3fl/PV-Cre + Rescue, 2.13 ± 0.17, 1.9 ± 0.17, 1.6 ± 0.1, 1.3 ± 0.1, n = 8 cells; p > 0.05 rescue vs control for all ISI). (PV-Cre and NL3fl/PV-Cre data from Fig 2b.) c-e, Inhibition of excitatory synaptic transmission by the Gr-III mGluR agonist L-AP4 is rescued by the expression of NL3 in NL3fl/PV-Cre cells. c, (left) time course of normalized AMPAR EPSCs during application of L-AP4 and sample EPSCs in response to paired-pulse stimulation before and after L-AP4 application (right) in PV-Cre (before-black, after-blue), NL3fl/PV-Cre (before-orange, after-green) and NL3fl/PV-Cre-DIO-NL3 (rescue: before-brown, after-green). d, Normalized summary plot (i) and EPSC amplitudes (ii) (NL3fl/PV-Cre-DIO-NL3: 0.58 ± 0.1, n = 6, p > 0.1), e, Normalized PPR changes (NL3fl/PV-Cre-DIO-NL3: 1.3 ± 0.1, n = 7, p > 0.1 vs PV-Cre) (i) and PPR (ii) values in response to L-AP4 application in NL3fl/PV-Cre-DIO-NL3 cells. (PV-Cre and NL3fl/PV-Cre data from Fig. 3i-l.)

Supplementary Figure 10 Performance in a reward alternation task and locomotor activity are not affected by deletion of NL3 from PV cells.

a. Schematic representation of a reward alternation task in a T maze (left). PV-Cre and NL3fl/PV-Cre mice make similar %correct choices after 6 days of training in the T maze (PV-Cre, 78 ± 4% n = 7; NL3fl/PV-Cre, 74 ± 4, n = 7). b, total distance travelled on the force plate in 20 min (84.9 ± 4.2 m for NL3PVcre+/+, n = 5 and 77.7 ± 2.1 m for NL3fl/PV-Cre, n = 7). c, number of low motion bouts in a 20 min session (14.6 ± 2.1 for NL3PVcre+/+, n = 5 and 21.8 ± 3.8 for NL3fl/PV-Cre, n = 7). d, average stereotypic score (1683 ± 242 for NL3PVcre+/+, n = 5 and 1430 ± 133 for NL3fl/PV-Cre, n = 7).

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Polepalli, J., Wu, H., Goswami, D. et al. Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Nat Neurosci 20, 219–229 (2017). https://doi.org/10.1038/nn.4471

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