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Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity

Abstract

Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors. MGE-derived interneuron synapses were dominated by GluA2-lacking AMPA-type glutamate receptors (AMPARs), with little contribution from NMDA-type receptors (NMDARs) throughout development. In contrast, CGE-derived cell synapses had large NMDAR components and used GluA2-containing AMPARs. In neonates, both MGE- and CGE-derived interneurons expressed primarily GluN2B subunit–containing NMDARs, which most CGE-derived interneurons retained into adulthood. However, MGE-derived interneuron NMDARs underwent a GluN2B-to-GluN2A switch that could be triggered acutely with repetitive synaptic activity. Our findings establish ganglionic eminence–dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells.

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Figure 1: MGE- and CGE-dependent expression of synaptic glutamate receptors.
Figure 2: MGE and CGE specification of synaptic glutamate receptor expression is maintained through early development.
Figure 3: Developmental expression of synaptic GluN2 is cell-type specific.
Figure 4: Afferent specificity of glutamatergic transmission maturation in MGE-derived cells.
Figure 5: GluN2B-containing NMDARs participate in summation and spike timing of young MGE-derived interneurons.
Figure 6: An activity-dependent change in GluN2 subunit expression in neonatal MGE-derived cells.
Figure 7: Principal-cell bursting activity in CA3 evokes a rapid GluN2 subunit switch in MGE-derived neonatal basket and bistratified cells.

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References

  1. Isaac, J.T. Postsynaptic silent synapses: evidence and mechanisms. Neuropharmacology 45, 450–460 (2003).

    Article  CAS  Google Scholar 

  2. Pickard, L. et al. Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes. Neuropharmacology 41, 700–713 (2001).

    Article  CAS  Google Scholar 

  3. Eybalin, M., Caicedo, A., Renard, N., Ruel, J. & Puel, J.L. Transient Ca2+-permeable AMPA receptors in postnatal rat primary auditory neurons. Eur. J. Neurosci. 20, 2981–2989 (2004).

    Article  Google Scholar 

  4. Kumar, S.S., Bacci, A., Kharazia, V. & Huguenard, J.R. A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J. Neurosci. 22, 3005–3015 (2002).

    Article  CAS  Google Scholar 

  5. Sheng, M., Cummings, J., Roldan, L.A., Jan, Y.N. & Jan, L.Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368, 144–147 (1994).

    Article  CAS  Google Scholar 

  6. Bellone, C. & Nicoll, R.A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007).

    Article  CAS  Google Scholar 

  7. Bellone, C., Mameli, M. & Luscher, C. In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. Nat. Neurosci. 14, 1439–1446 (2011).

    Article  CAS  Google Scholar 

  8. Matta, J.A., Ashby, M.C., Sanz-Clemente, A., Roche, K.W. & Isaac, J.T. mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron 70, 339–351 (2011).

    Article  CAS  Google Scholar 

  9. Sanz-Clemente, A., Matta, J.A., Isaac, J.T. & Roche, K.W. Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors. Neuron 67, 984–996 (2010).

    Article  CAS  Google Scholar 

  10. Quinlan, E.M., Philpot, B.D., Huganir, R.L. & Bear, M.F. Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat. Neurosci. 2, 352–357 (1999).

    Article  CAS  Google Scholar 

  11. Somogyi, P. & Klausberger, T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J. Physiol. (Lond.) 562, 9–26 (2005).

    Article  CAS  Google Scholar 

  12. Korotkova, T., Fuchs, E.C., Ponomarenko, A., von Engelhardt, J. & Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68, 557–569 (2010).

    Article  CAS  Google Scholar 

  13. Fuchs, E.C. et al. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron 53, 591–604 (2007).

    Article  CAS  Google Scholar 

  14. Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).

    Article  CAS  Google Scholar 

  15. Tricoire, L. et al. A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity. J. Neurosci. 31, 10948–10970 (2011).

    Article  CAS  Google Scholar 

  16. Vucurovic, K. et al. Serotonin 3A receptor subtype as an early and protracted marker of cortical interneuron subpopulations. Cereb. Cortex 20, 2333–2347 (2010).

    Article  Google Scholar 

  17. Lee, S., Hjerling-Leffler, J., Zagha, E., Fishell, G. & Rudy, B. The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J. Neurosci. 30, 16796–16808 (2010).

    Article  CAS  Google Scholar 

  18. Traynelis, S.F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

    Article  CAS  Google Scholar 

  19. Daw, M.I., Tricoire, L., Erdelyi, F., Szabo, G. & McBain, C.J. Asynchronous transmitter release from cholecystokinin-containing inhibitory interneurons is widespread and target-cell independent. J. Neurosci. 29, 11112–11122 (2009).

    Article  CAS  Google Scholar 

  20. Morozov, Y.M., Torii, M. & Rakic, P. Origin, early commitment, migratory routes, and destination of cannabinoid type 1 receptor-containing interneurons. Cereb. Cortex 19 (suppl. 1): 78–89 (2009).

    Article  Google Scholar 

  21. Williams, K., Russell, S.L., Shen, Y.M. & Molinoff, P.B. Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron 10, 267–278 (1993).

    Article  CAS  Google Scholar 

  22. Chavis, P. & Westbrook, G. Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411, 317–321 (2001).

    Article  CAS  Google Scholar 

  23. Ito, I., Kawakami, R., Sakimura, K., Mishina, M. & Sugiyama, H. Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses. Neuropharmacology 39, 943–951 (2000).

    Article  CAS  Google Scholar 

  24. Lei, S. & McBain, C.J. Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses. Neuron 33, 921–933 (2002).

    Article  CAS  Google Scholar 

  25. Tóth, K. & McBain, C.J. Afferent-specific innervation of two distinct AMPA receptor subtypes on single hippocampal interneurons. Nat. Neurosci. 1, 572–578 (1998).

    Article  Google Scholar 

  26. Philpot, B.D., Sekhar, A.K., Shouval, H.Z. & Bear, M.F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).

    Article  CAS  Google Scholar 

  27. Mierau, S.B., Meredith, R.M., Upton, A.L. & Paulsen, O. Dissociation of experience-dependent and -independent changes in excitatory synaptic transmission during development of barrel cortex. Proc. Natl. Acad. Sci. USA 101, 15518–15523 (2004).

    Article  CAS  Google Scholar 

  28. Mahanty, N.K. & Sah, P. Calcium-permeable AMPA receptors mediate long-term potentiation in interneurons in the amygdala. Nature 394, 683–687 (1998).

    Article  CAS  Google Scholar 

  29. Oren, I., Nissen, W., Kullmann, D.M., Somogyi, P. & Lamsa, K.P. Role of ionotropic glutamate receptors in long-term potentiation in rat hippocampal CA1 oriens-lacunosum moleculare interneurons. J. Neurosci. 29, 939–950 (2009).

    Article  CAS  Google Scholar 

  30. McMahon, L.L. & Kauer, J.A. Hippocampal interneurons express a novel form of synaptic plasticity. Neuron 18, 295–305 (1997).

    Article  CAS  Google Scholar 

  31. Miles, R. & Wong, R.K. Single neurones can initiate synchronized population discharge in the hippocampus. Nature 306, 371–373 (1983).

    Article  CAS  Google Scholar 

  32. Stoop, R., Conquet, F., Zuber, B., Voronin, L.L. & Pralong, E. Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections. J. Neurosci. 23, 5634–5644 (2003).

    Article  CAS  Google Scholar 

  33. Ho, M.T. et al. Burst firing induces postsynaptic LTD at developing mossy fibre-CA3 pyramid synapses. J. Physiol. (Lond.) 587, 4441–4454 (2009); erratum 587, 5798 (2009).

    Article  CAS  Google Scholar 

  34. Sanchez-Vives, M.V. & McCormick, D.A. Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat. Neurosci. 3, 1027–1034 (2000).

    Article  CAS  Google Scholar 

  35. Durand, G.M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).

    Article  CAS  Google Scholar 

  36. Zhang, L. & Warren, R.A. Postnatal development of excitatory postsynaptic currents in nucleus accumbens medium spiny neurons. Neuroscience 154, 1440–1449 (2008).

    Article  CAS  Google Scholar 

  37. Isaac, J.T., Crair, M.C., Nicoll, R.A. & Malenka, R.C. Silent synapses during development of thalamocortical inputs. Neuron 18, 269–280 (1997).

    Article  CAS  Google Scholar 

  38. Kerchner, G.A. & Nicoll, R.A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813–825 (2008).

    Article  CAS  Google Scholar 

  39. McBain, C.J. & Dingledine, R. Heterogeneity of synaptic glutamate receptors on CA3 stratum radiatum interneurones of rat hippocampus. J. Physiol. (Lond.) 462, 373–392 (1993).

    Article  CAS  Google Scholar 

  40. Morin, F., Beaulieu, C. & Lacaille, J.C. Membrane properties and synaptic currents evoked in CA1 interneuron subtypes in rat hippocampal slices. J. Neurophysiol. 76, 1–16 (1996).

    Article  CAS  Google Scholar 

  41. Petralia, R.S., Wang, Y.X., Mayat, E. & Wenthold, R.J. Glutamate receptor subunit 2–selective antibody shows a differential distribution of calcium-impermeable AMPA receptors among populations of neurons. J. Comp. Neurol. 385, 456–476 (1997).

    Article  CAS  Google Scholar 

  42. Catania, M.V. et al. AMPA receptor subunits are differentially expressed in parvalbumin- and calretinin-positive neurons of the rat hippocampus. Eur. J. Neurosci. 10, 3479–3490 (1998).

    Article  CAS  Google Scholar 

  43. Tóth, K. & McBain, C.J. Target-specific expression of pre- and postsynaptic mechanisms. J. Physiol. (Lond.) 525, 41–51 (2000).

    Article  Google Scholar 

  44. Topolnik, L., Congar, P. & Lacaille, J.C. Differential regulation of metabotropic glutamate receptor– and AMPA receptor–mediated dendritic Ca2+ signals by presynaptic and postsynaptic activity in hippocampal interneurons. J. Neurosci. 25, 990–1001 (2005).

    Article  CAS  Google Scholar 

  45. Kullmann, D.M. & Lamsa, K.P. Long-term synaptic plasticity in hippocampal interneurons. Nat. Rev. Neurosci. 8, 687–699 (2007).

    Article  CAS  Google Scholar 

  46. Szabo, A. et al. Calcium-permeable AMPA receptors provide a common mechanism for LTP in glutamatergic synapses of distinct hippocampal interneuron types. J. Neurosci. 32, 6511–6516 (2012).

    Article  CAS  Google Scholar 

  47. Nissen, W., Szabo, A., Somogyi, J., Somogyi, P. & Lamsa, K.P. Cell type–specific long-term plasticity at glutamatergic synapses onto hippocampal interneurons expressing either parvalbumin or CB1 cannabinoid receptor. J. Neurosci. 30, 1337–1347 (2010).

    Article  CAS  Google Scholar 

  48. Doischer, D. et al. Postnatal differentiation of basket cells from slow to fast signaling devices. J. Neurosci. 28, 12956–12968 (2008).

    Article  CAS  Google Scholar 

  49. Belforte, J.E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat. Neurosci. 13, 76–83 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

D. Abebe and X. Yuan provided expert technical assistance. We thank S. Anderson (University of Pennsylvania) for providing the Nkx2-1-cre driver line and G. Fishell (New York University) for providing the RCE reporter line. This work was supported by a Eunice Kennedy-Shriver National Institute of Child Health and Human Development intramural award to C.J.M. and a PRAT Fellowship to J.A.M.

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J.A.M., K.A.P. and C.J.M. conceived of the project, designed experiments and wrote the manuscript. J.A.M., K.A.P., M.T.C. and R.C. conducted experiments and analyzed the data. B.W.J. provided technical assistance with cell recoveries and drawings. C.J.M. and K.A.P. supervised the project.

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Correspondence to Kenneth A Pelkey.

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Matta, J., Pelkey, K., Craig, M. et al. Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat Neurosci 16, 1032–1041 (2013). https://doi.org/10.1038/nn.3459

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