Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Synapses formed by normal and abnormal hippocampal mossy fibers

  • 861 Accesses

  • 39 Citations


The axon terminals (mossy fibers) of hippocampal dentate granule cells form characteristic synaptic connections with large spines or excrescences of both hilar mossy cells and CA3 pyramidal neurons. Interneurons of the hilar region and area CA3 are also prominent targets of mossy fibers. The tracing of biocytin-filled mossy fibers and immunolabeling of target cells with interneuron markers has revealed that the majority of mossy fiber synapses project to γ aminobutyric acid (GABA)-ergic inhibitory interneurons rather than to excitatory principal cells, although the functional implications of these quantitative differences are unclear. Following a brief description of the “classical” mossy fiber synapse on excrescences of CA3 pyramidal cells, the present review focuses on the contacts formed between granule cells and GABAergic interneurons, both normally and after synaptic reorganization. In response to deafferentation of mossy cell target cells, which include both granule cells and interneurons, mossy fibers “sprout” new axon collaterals that form a band of supragranular mossy fibers in the inner molecular layer of the dentate gyrus. Although most newly formed recurrent mossy fibers establish synapses with granule cells, there is an apparently convergent input of new mossy fibers onto GABA-immunoreactive interneuron dendrites that traverse the inner molecular layer. These mossy fiber-interneuron synapses in the dentate gyrus are observed in chronically epileptic rats and may be the structural correlate of the granule cell hyperinhibition observed in these animals in vivo. Together, the findings reviewed here establish mossy fiber synapses as an important component of inhibitory circuits in the hippocampus.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. Acsády L, Kamondi A, Sík A, Freund T, Buzsáki G (1998) GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J Neurosci 18:3386–3403

  2. Amaral DG (1978) A Golgi study of cell types in the hilar region of the hippocampus in the rat. J Comp Neurol 182:851–914

  3. Andersen P, Bliss TVP, Skrede KK (1971) Lamellar organization of hippocampal excitatory pathways. Exp Brain Res 13:222–238

  4. Bender R, Heimrich B, Meyer M, Frotscher M (1998) Hippocampal mossy fiber sprouting is not impaired in brain-derived neurotrophic factor-deficient mice. Exp Brain Res 120:399–402

  5. Bischofberger J, Engel D, Frotscher M, Jonas P (2006) Mechanisms underlying the efficacy of transmitter release at mossy fiber synapses in the hippocampal network. Pflügers Arch (in press)

  6. Blackstad TW (1956) Commissural connections of the hippocampal region of the rat, with special reference to their mode of termination. J Comp Neurol 105:417–537

  7. Blackstad TW (1958) On the termination of some afferents to the hippocampus and fascia dentata: an experimental study in the rat. Acta Anat (Basel) 35:202–214

  8. Blackstad TW, Kjaerheim A (1961) Special axodendritic synapses in the hippocampal cortex: electron and light microscopic studies on the layer of mossy fibers. J Comp Neurol 117:113–159

  9. Blümcke I, Suter B, Behle K, Kuhn R, Schramm J, Elger CE, Wiestler OD (2000) Loss of hilar mossy cells in Ammon’s horn sclerosis. Epilepsia 41 (Suppl 6):S174–S180

  10. Cherlow DG, Dymond AM, Crandall PH, Walter RD, Serafetinides EA (1977) Evoked response and after-discharge thresholds to electrical stimulation in temporal lobe epileptics. Arch Neurol 34:527–531

  11. Chicurel ME, Harris KM (1992) Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the hippocampus. J Comp Neurol 325:169–182

  12. Colder BW, Wilson CL, Frysinger RC, Chao LC, Harper RM, Engel J Jr (1996) Neuronal synchrony in relation to burst discharge in epileptic human temporal lobes. J Neurophysiol 75:2496–2508

  13. Danzer SC, He X, McNamara JO (2004) Ontogeny of seizure-induced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus. Hippocampus 14:345–355

  14. Deller T, Leranth C (1990) Synaptic connections of neuropeptide Y (NPY) immunoreactive neurons in the hilar area of the rat hippocampus. J Comp Neurol 300:433–447

  15. Eccles JC (1973) The understanding of the brain. McGraw-Hill, New York

  16. Fairén A, Peters A, Saldanha J (1977) A new procedure for examining Golgi impregnated neurons by light and electron microscopy. J Neurocytol 6:311–337

  17. Förster E, Zhao S, Frotscher M (2006) Laminating the hippocampus. Nat Rev Neurosci 7:259–267

  18. Frotscher M (1985) Mossy fibres form synapses with identified pyramidal basket cells in the CA3 region of the guinea pig hippocampus: a combined Golgi-electron microscope study. J Neurocytol 14:245–259

  19. Frotscher M (1989) Mossy fiber synapses on glutamate decarboxylase-immunoreactive neurons: evidence for feed-forward inhibition in the CA3 region of the hippocampus. Exp Brain Res 75:441–445

  20. Frotscher M, Zimmer J (1983) Lesion-induced mossy fibers to the molecular layer of the rat fascia dentata: identification of postsynaptic granule cells by the Golgi/EM technique. J Comp Neurol 215:299–311

  21. Frotscher M, Soriano E, Misgeld U (1994) Divergence of hippocampal mossy fibers. Synapse 16:148–160

  22. Golgi C (1886) Sulla fina anatomica degli organi centrali del sistema nervoso. Hoepli, Milan

  23. Gulyas AI, Miettinen R, Jacobowitz DM, Freund TF (1992) Calretinin is present in non-pyramidal cells of the rat hippocampus. I. A new type of neuron specifically associated with the mossy fibre system. Neuroscience 48:1–27

  24. Gutierrez R (2005) The dual glutamatergic-GABAergic phenotype of hippocampal granule cells. Trends Neurosci 28:297–303

  25. Halasy K, Somogyi P (1993) Subdivisions in the multiple GABAergic innervation of granule cells in the dentate gyrus of the rat hippocampus. Eur J Neurosci 5:411–429

  26. Hamlyn LH (1962) The fine structure of the mossy fibre endings in the hippocampus of the rabbit. J Anat 97:112–120

  27. Henze DA, Urban NN, Barrionuevo G (2000) The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98:407–427

  28. Koelliker A (1896) Handbuch der Gewebelehre des Menschen. Zweiter Band: Nervensystem des Menschen und der Thiere. Wilhelm Engelmann, Leipzig

  29. Laurberg S, Zimmer J (1981) Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats. J Comp Neurol 200:433–459

  30. Leranth C, Frotscher M (1986) Synaptic connections of cholecystokinin-immunoreactive neurons and terminals in the rat fascia dentata: a combined light and electron microscopic study. J Comp Neurol 254:51–64

  31. Lorente de Nó R (1934) Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J Psychol Neurol 46:113–177

  32. Nadler JV, Perry BW, Cotman CW (1978) Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271:676–677

  33. Nadler JV, Perry BW, Cotman CW (1980) Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3–CA4 afferents with kainic acid. Brain Res 182:1–9

  34. Otal R, Martinez A, Soriano E (2005) Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossy fiber terminals in the hippocampus. Cell Tissue Res 319:349–358

  35. Ramón y Cajal SR (1911) Histologie du Système Nerveux de l’Homme et des Vertébrés, vol. II. Maloine, Paris

  36. Sätzler K, Söhl LF, Bollmann JH, Borst JGB, Frotscher M, Sakmann B, Lübke JHR (2002) Three-dimensional reconstruction of a calyx of Held and its postsynaptic principal neuron in the medial nucleus of the trapezoid body. J Neurosci 22:10567–10579

  37. Schmidt-Hieber C, Jonas P, Bischofberger J (2004) Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429:184–187

  38. Seress L, Frotscher M (1990) Morphological variability is a characteristic feature of granule cells in the primate fascia dentate: a combined Golgi/electron microscope study. J Comp Neurol 293:253–267

  39. Sloviter RS (1987) Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235:73–76

  40. Sloviter RS (2003) Excitatory dentate granule cells normally contain GAD and GABA, but does that make them GABAergic, and do seizures shift granule cell function in the inhibitory direction? Epilepsy Curr 3:3–5

  41. Sloviter RS, Valiquette G, Abrams GM, Ronk EC, Sollas AL, Paul LA, Neubort S (1989) Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243:535–538

  42. Sloviter RS, Dichter MA, Rachinsky TL, Dean E, Goodman JH, Sollas AL, Martin DL (1996) Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol 373:593–618

  43. Sloviter RS, Zappone CA, Harvey BD, Frotscher M (2006) Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory interneurons: possible anatomical substrate of granule cell hyperinhibition in chronically epileptic rats. J Comp Neurol 494:944–960

  44. Soriano E, Frotscher M (1989) A GABAergic axo-axonic cell in the fascia dentata controls the main excitatory hippocampal pathway. Brain Res 503:170–174

  45. Soriano E, Frotscher M (1993a) Spiny nonpyramidal neurons in the CA3 region of the rat hippocampus are glutamate-like immunoreactive and receive convergent mossy fiber input. J Comp Neurol 332:435–448

  46. Soriano E, Frotscher M (1993b) GABAergic innervation of the rat fascia dentata: a novel type of interneuron in the granule cell layer with extensive axonal arborization in the molecular layer. J Comp Neurol 334:385–396

  47. Storm-Mathisen J (1981) Glutamate in hippocampal pathways. Adv Biochem Psychopharmacol 27:43–55

  48. Tauck DL, Nadler JV (1985) Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 5:1016–1022

  49. Terrian DM, Gannon RL, Rea MA (1990) Glutamate is the endogenous amino acid selectively released by rat hippocampal mossy fiber synaptosomes concomitantly with prodynorphin-derived peptides. Neurochem Res 15:1–5

  50. Timm F (1958) Zur Histochemie der Schwermetalle, das Sulfid-Silber-Verfahren. Dtsch Z Gesamte Gerichtl Med 46:706–711

  51. Vida I, Frotscher M (2000) A hippocampal interneuron associated with the mossy fiber system. Proc Natl Acad Sci USA 97:1275–1280

  52. Wilson CL, Khan SU, Engel J Jr, Isokawa M, Babb TL, Behnke EJ (1998) Paired pulse suppression and facilitation in human epileptogenic hippocampal formation. Epilepsy Res 31:211–230

Download references

Author information

Correspondence to Michael Frotscher.

Additional information

The work at the authors’ laboratories is supported by the Deutsche Forschungsgemeinschaft (Transregio Sonderforschungsbereich TR-3, to M.F.), and NIH-NINDS (grant no. NS 18201, to R.S.S.). We thank Sigrun Nestel for excellent technical assistance.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Frotscher, M., Jonas, P. & Sloviter, R.S. Synapses formed by normal and abnormal hippocampal mossy fibers. Cell Tissue Res 326, 361–367 (2006). https://doi.org/10.1007/s00441-006-0269-2

Download citation


  • Mossy fiber synapse
  • CA3 pyramidal cells
  • Dentate gyrus granule cells
  • Hippocampal interneurons
  • Mossy cells
  • Mossy fiber sprouting