Hyper-diversity of CRH interneurons in mouse hippocampus

Abstract

Hippocampal inhibitory interneurons comprise an anatomically, neurochemically and electrophysiologically diverse population of cells that are essential for the generation of the oscillatory activity underlying hippocampal spatial and episodic memory processes. Here, we aimed to characterize a population of interneurons that express the stress-related neuropeptide corticotropin-releasing hormone (CRH) within existing interneuronal categories through the use of combined electrophysiological and immunocytochemical approaches. Focusing on CA1 strata pyramidale and radiatum of mouse hippocampus, CRH interneurons were found to exhibit a heterogeneous neurochemical phenotype with parvalbumin, cholecystokinin and calretinin co-expression observed to varying degrees. In contrast, CRH and somatostatin were never co-expressed. Electrophysiological categorization identified heterogeneous firing pattern of CRH neurons, with two distinct subtypes within stratum pyramidale and stratum radiatum. Together, these findings indicate that CRH-expressing interneurons do not segregate into any single distinct subtype of interneuron using conventional criteria. Rather our findings suggest that CRH is likely co-expressed in subpopulations of previously described hippocampal interneurons. In addition, the observed heterogeneity suggests that distinct CRH interneuron subtypes may have specific functional roles in the both physiological and pathophysiological hippocampal processes.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Aldenhoff JB, Gruol DL, Rivier J, Vale W, Siggins GR (1983) Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science 221:875–877

    Article  CAS  PubMed  Google Scholar 

  2. Bartos M, Vida I, Jonas P (2007) Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56

    Article  CAS  PubMed  Google Scholar 

  3. Brown DA, Adams PR (1980) Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 283:673–676

    Article  CAS  PubMed  Google Scholar 

  4. Buhl EH, Han ZS, Lorinczi Z, Stezhka VV, Karnup SV, Somogyi P (1994) Physiological properties of anatomically identified axo-axonic cells in the rat hippocampus. J Neurophysiol 71:1289–1307

    Article  CAS  PubMed  Google Scholar 

  5. Buhl EH, Szilagyi T, Halasy K, Somogyi P (1996) Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro. Hippocampus 6:294–305

    Article  CAS  PubMed  Google Scholar 

  6. Chen Y, Brunson KL, Muller MB, Cariaga W, Baram TZ (2000) Immunocytochemical distribution of corticotropin-releasing hormone receptor type-1 (CRF(1))-like immunoreactivity in the mouse brain: light microscopy analysis using an antibody directed against the C-terminus. J Comp Neurol 420:305–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen Y, Brunson KL, Adelmann G, Bender RA, Frotscher M, Baram TZ (2004) Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience 126:533–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Y, Rex CS, Rice CJ, Dube CM, Gall CM, Lynch G, Baram TZ (2010) Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci USA 107:13123–13128

    Article  PubMed  Google Scholar 

  10. Chen Y, Andres AL, Frotscher M, Baram TZ (2012) Tuning synaptic transmission in the hippocampus by stress: the CRH system. Front Cell Neurosci 6:13

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen Y, Molet J, Gunn BG, Ressler K, Baram TZ (2015) Diversity of reporter expression patterns in transgenic mouse lines targeting corticotropin-releasing hormone-expressing neurons. Endocrinology 156:4769–4780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen Y, Molet J, Lauterborn JC, Trieu BH, Bolton JL, Patterson KP, Gall CM, Lynch G, Baram TZ (2016) Converging, synergistic actions of multiple stress hormones mediate enduring memory impairments after acute simultaneous stresses. J Neurosci 36:11295–11307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cobb SR, Buhl EH, Halasy K, Paulsen O, Somogyi P (1995) Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378:75–78

    Article  CAS  PubMed  Google Scholar 

  14. Colgin LL (2016) Rhythms of the hippocampal network. Nat Rev Neurosci 17:239–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cossart R, Petanjek Z, Dumitriu D, Hirsch JC, Ben-Ari Y, Esclapez M, Bernard C (2006) Interneurons targeting similar layers receive synaptic inputs with similar kinetics. Hippocampus 16:408–420

    Article  PubMed  Google Scholar 

  16. Dedic N, Kuhne C, Jakovcevski M, Hartmann J, Genewsky AJ, Gomes KS, Anderzhanova E, Pohlmann ML, Chang S, Kolarz A, Vogl AM, Dine J, Metzger MW, Schmid B, Almada RC, Ressler KJ, Wotjak CT, Grinevich V, Chen A, Schmidt MV, Wurst W, Refojo D, Deussing JM (2018) Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety. Nat Neurosci 21:803–807

    Article  CAS  PubMed  Google Scholar 

  17. Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6:215–229

    Article  CAS  PubMed  Google Scholar 

  18. Fleidervish IA, Friedman A, Gutnick MJ (1996) Slow inactivation of Na + current and slow cumulative spike adaptation in mouse and guinea-pig neocortical neurones in slices. J Physiol 493(Pt 1):83–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470

    Article  CAS  PubMed  Google Scholar 

  20. Fuentealba P, Begum R, Capogna M, Jinno S, Marton LF, Csicsvari J, Thomson A, Somogyi P, Klausberger T (2008) Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57:917–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gulyas AI, Hajos N, Freund TF (1996) Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J Neurosci 16:3397–3411

    Article  CAS  PubMed  Google Scholar 

  22. Gunn BG, Baram TZ (2017) Stress and seizures: space, time and hippocampal circuits. Trends Neurosci 40:667–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gunn BG, Cox CD, Chen Y, Frotscher M, Gall CM, Baram TZ, Lynch G (2017) The endogenous stress hormone CRH modulates excitatory transmission and network physiology in hippocampus. Cereb Cortex 27:4182–4198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Haug T, Storm JF (2000) Protein kinase A mediates the modulation of the slow Ca(2+)-dependent K(+) current, I(sAHP), by the neuropeptides CRF, VIP, and CGRP in hippocampal pyramidal neurons. J Neurophysiol 83:2071–2079

    Article  CAS  PubMed  Google Scholar 

  25. Hooper A, Maguire J (2016) Characterization of a novel subtype of hippocampal interneurons that express corticotropin-releasing hormone. Hippocampus 26:41–53

    Article  CAS  PubMed  Google Scholar 

  26. Hooper A, Fuller PM, Maguire J (2018) Hippocampal corticotropin-releasing hormone neurons support recognition memory and modulate hippocampal excitability. PLoS One 13:e0191363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hu H, Gan J, Jonas P (2014) Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 345:1255263

    Article  CAS  PubMed  Google Scholar 

  28. Isaacson JS, Scanziani M (2011) How inhibition shapes cortical activity. Neuron 72:231–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ivy AS, Rex CS, Chen Y, Dube C, Maras PM, Grigoriadis DE, Gall CM, Lynch G, Baram TZ (2010) Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 30:13005–13015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Joels M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10:459–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Klausberger T, Somogyi P (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321:53–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Klausberger T, Magill PJ, Marton LF, Roberts JD, Cobden PM, Buzsaki G, Somogyi P (2003) Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421:844–848

    Article  CAS  PubMed  Google Scholar 

  33. Klausberger T, Marton LF, Baude A, Roberts JD, Magill PJ, Somogyi P (2004) Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo. Nat Neurosci 7:41–47

    Article  CAS  PubMed  Google Scholar 

  34. Kono J, Konno K, Talukder AH, Fuse T, Abe M, Uchida K, Horio S, Sakimura K, Watanabe M, Itoi K (2017) Distribution of corticotropin-releasing factor neurons in the mouse brain: a study using corticotropin-releasing factor-modified yellow fluorescent protein knock-in mouse. Brain Struc Funct 222:1705–1732

    Article  CAS  Google Scholar 

  35. Kratzer S, Mattusch C, Metzger MW, Dedic N, Noll-Hussong M, Kafitz KW, Eder M, Deussing JM, Holsboer F, Kochs E, Rammes G (2013) Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels. Front Cell Neurosci 7:91

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lovett-Barron M, Turi GF, Kaifosh P, Lee PH, Bolze F, Sun XH, Nicoud JF, Zemelman BV, Sternson SM, Losonczy A (2012) Regulation of neuronal input transformations by tunable dendritic inhibition. Nat Neurosci 15:423–430, S421–S423

    Article  CAS  PubMed  Google Scholar 

  37. Madison DV, Nicoll RA (1984) Control of the repetitive discharge of rat CA 1 pyramidal neurones in vitro. J Physiol 354:319–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin EI, Ressler KJ, Jasnow AM, Dabrowska J, Hazra R, Rainnie DG, Nemeroff CB, Owens MJ (2010) A novel transgenic mouse for gene-targeting within cells that express corticotropin-releasing factor. Biol Psychiatry 67:1212–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Miles R, Toth K, Gulyas AI, Hajos N, Freund TF (1996) Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16:815–823

    Article  CAS  PubMed  Google Scholar 

  40. Mody I, Pearce RA (2004) Diversity of inhibitory neurotransmission through GABA(A) receptors. Trends Neurosci 27:569–575

    Article  CAS  PubMed  Google Scholar 

  41. Neher E (1992) Correction for liquid junction potentials in patch clamp experiments. Methods Enzymol 207:123–131

    Article  CAS  PubMed  Google Scholar 

  42. Neves G, Cooke SF, Bliss TV (2008) Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9:65–75

    Article  CAS  PubMed  Google Scholar 

  43. Pawelzik H, Hughes DI, Thomson AM (2002) Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus. J Comp Neurol 443:346–367

    Article  PubMed  Google Scholar 

  44. Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ (2017) Hippocampal GABAergic inhibitory interneurons. Physiol Rev 97:1619–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Peng J, Long B, Yuan J, Peng X, Ni H, Li X, Gong H, Luo Q, Li A (2017) A quantitative analysis of the distribution of CRH neurons in whole mouse brain. Front Neuroanat 11:63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van den Pol AN (2012) Neuropeptide transmission in brain circuits. Neuron 76:98–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schutz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333:1903–1907

    Article  CAS  PubMed  Google Scholar 

  48. Roux L, Buzsaki G (2015) Tasks for inhibitory interneurons in intact brain circuits. Neuropharmacology 88:10–23

    Article  CAS  PubMed  Google Scholar 

  49. Royer S, Zemelman BV, Losonczy A, Kim J, Chance F, Magee JC, Buzsaki G (2012) Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. Nat Neurosci 15:769–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sarkar J, Wakefield S, MacKenzie G, Moss SJ, Maguire J (2011) Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J Neurosci 31:18198–18210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stocker M (2004) Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci 5:758–770

    Article  CAS  PubMed  Google Scholar 

  52. Toth K, Suares G, Lawrence JJ, Philips-Tansey E, McBain CJ (2000) Differential mechanisms of transmission at three types of mossy fiber synapse. J Neurosci 20:8279–8289

    Article  CAS  PubMed  Google Scholar 

  53. Tricoire L, Pelkey KA, Erkkila BE, Jeffries BW, Yuan X, McBain CJ (2011) A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity. J Neurosci 31:10948–10970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Walker LC, Cornish LC, Lawrence AJ, Campbell EJ (2018) The effect of acute or repeated stress on the corticotropin releasing factor system in the CRH-IRES-Cre mouse: a validation study. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2018.09.037 (Epub ahead of print)

    Article  PubMed  Google Scholar 

  55. Yan XX, Baram TZ, Gerth A, Schultz L, Ribak CE (1998a) Co-localization of corticotropin-releasing hormone with glutamate decarboxylase and calcium-binding proteins in infant rat neocortical interneurons. Exp Brain Res 123:334–340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yan XX, Toth Z, Schultz L, Ribak CE, Baram TZ (1998b) Corticotropin-releasing hormone (CRH)-containing neurons in the immature rat hippocampal formation: light and electron microscopic features and colocalization with glutamate decarboxylase and parvalbumin. Hippocampus 8:231–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

National Institutes of Health, NS28912, MH096889, MH73136.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Tallie Z. Baram or Yuncai Chen.

Ethics declarations

Conflict of interest

Authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gunn, B.G., Sanchez, G.A., Lynch, G. et al. Hyper-diversity of CRH interneurons in mouse hippocampus. Brain Struct Funct 224, 583–598 (2019). https://doi.org/10.1007/s00429-018-1793-z

Download citation

Keywords

  • Hippocampus
  • Interneuron
  • CRH
  • Stress