Trends in Neurosciences
Volume 25, Issue 3, 1 March 2002, Pages 140-144
Journal home page for Trends in Neurosciences

Opinion
Mossy cells in epilepsy: rigor mortis or vigor mortis?

https://doi.org/10.1016/S0166-2236(00)02122-6Get rights and content

Abstract

Mossy cells are bi-directionally connected through a positive feedback loop to granule cells, the principal cells of the dentate gyrus. This recurrent circuit is strategically placed between the entorhinal cortex and the hippocampal CA3 region. In spite of their potentially pro-convulsive arrangement with granule cells, mossy cells have not been seriously considered to promote seizures, because mossy cells, allegedly one of the most vulnerable cell types in the entire mammalian brain, have long been ‘known’ to die en masse in epilepsy. However, new data suggest that rumors of the rapid demise of the mossy cells might have been greatly exaggerated.

Section snippets

Mossy cells: a case of neurons living dangerously?

A caricature of mossy cells is that they are so vulnerable they behave like fuses, and that their rapid death breaks the circuit after a dangerous surge in electrical activity in the network [21]. What are the mossy cell properties that could enable these cells to blow so easily and serve as self-sacrificing neuronal fuses? First and foremost, mossy cells give and receive excitatory synapses to and from granule cells, an arrangement that provides a positive feedback circuit 23, 24, 25, 26.

Mossy cells lost and found

Owing to the lack of mossy cell-specific neuronal markers, most of the data upon which the ideas of selective vulnerability and widespread loss of mossy cells rested are based on indirect evidence, such as equating hilar cell loss from Nissl stains with mossy cell loss or studying changes in the number of cells that lack expression for glutamate decarboxylase (GAD65/67), the synthesizing enzyme for the inhibitory neurotransmitter GABA. However, inferences based on such indirect approaches are

Can both loss and survival of mossy cells be pro-convulsive?

As far as the long-term decrease in threshold for seizures is concerned, is it the lost or the surviving mossy cells that are truly important? While the answer to this question remains to be determined, it is instructive to compare the predictions of three theories.

The first of these is essentially the ‘mossy cell loss causes mossy fiber sprouting’ hypothesis (Fig. 3a). As mossy fibers (the axons of granule cells) heavily innervate mossy cells, it has generally been believed that the loss of

Is the hilus half full or half empty in epilepsy?

Seizures beget seizures [58]; mossy fiber activity triggers mossy cell loss that triggers mossy fiber sprouting [45]; interneurons hyper-synchronize principal cells [59]; interneuronal heterogeneity regulates excitability [60]; increased inhibition 61, 62, 63, 64, 65, 66, 67, 68, 69 becomes converted to hyperexcitability [70]: these are just some of the challenging ideas that have arisen from recent results in epilepsy research. These possibilities vividly illustrate the web-like complexity and

Acknowledgements

This work was supported by the NIH (grant NS35915 to I.S.).

References (70)

  • R. Gutierrez et al.

    Synaptic reorganization in explanted cultures of rat hippocampus

    Brain Res.

    (1999)
  • B.M. Longo et al.

    Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats

    Neurosci. Lett.

    (1997)
  • C. Bernard

    Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis

    Epilepsy Res.

    (1998)
  • J.G. Jefferys et al.

    Dormant’ inhibitory neurons: do they exist and what is their functional impact?

    Epilepsy Res.

    (1998)
  • D.A. Prince et al.

    Inhibitory function in two models of chronic epileptogenesis

    Epilepsy Res.

    (1998)
  • R. Cossart

    Distribution of spontaneous currents along the somato-dendritic axis of rat hippocampal CA1 pyramidal neurons

    Neuroscience

    (2000)
  • D.A. Coulter

    Epilepsy-associated plasticity in gamma-aminobutyric acid receptor expression, function, and inhibitory synaptic properties

    Int. Rev. Neurobiol.

    (2001)
  • L. Wittner

    Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus

    Neuroscience

    (2001)
  • G.W. Mathern

    Quantified patterns of mossy fiber sprouting and neuron densities in hippocampal and lesional seizures

    J. Neurosurg.

    (1995)
  • B. El Bahh

    Correlations between granule cell dispersion, mossy fiber sprouting, and hippocampal cell loss in temporal lobe epilepsy

    Epilepsia

    (1999)
  • I. Blumcke

    Loss of hilar mossy cells in Ammon's horn sclerosis

    Epilepsia

    (2000)
  • F. Loup

    Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy

    J. Neurosci.

    (2000)
  • D.H. Lowenstein

    Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus

    J. Neurosci.

    (1992)
  • Z. Toth

    Instantaneous perturbation of dentate interneuronal networks by a pressure wave-transient delivered to the neocortex

    J. Neurosci.

    (1997)
  • T. Kotti

    The calretinin-containing mossy cells survive excitotoxic insult in the gerbil dentate gyrus. Comparison of excitotoxicity-induced neuropathological changes in the gerbil and rat

    Eur. J. Neurosci.

    (1996)
  • R.S. Sloviter

    Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the ‘dormant basket cell’ hypothesis and its possible relevance to temporal lobe epilepsy

    Hippocampus

    (1991)
  • J.E. Cavazos

    Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures

    J. Neurosci.

    (1994)
  • P.S. Buckmaster et al.

    Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats

    J. Neurosci.

    (1999)
  • M. Esclapez

    Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy

    J. Comp. Neurol.

    (1999)
  • D.G. Amaral

    A Golgi study of cell types in the hilar region of the hippocampus in the rat

    J. Comp. Neurol.

    (1978)
  • L. Seress et al.

    GABAergic cells in the dentate gyrus appear to be local circuit and projection neurons

    Exp. Brain Res.

    (1983)
  • H.E. Scharfman

    Blockade of excitation reveals inhibition of dentate spiny hilar neurons recorded in rat hippocampal slices

    J. Neurophysiol.

    (1992)
  • I. Soltesz et al.

    Patch-clamp recordings reveal powerful GABAergic inhibition in dentate hilar neurons

    J. Neurosci.

    (1994)
  • L. Acsady

    Unusual target selectivity of perisomatic inhibitory cells in the hilar region of the rat hippocampus

    J. Neurosci.

    (2000)
  • P.S. Buckmaster et al.

    Hippocampal mossy cell function: a speculative view

    Hippocampus

    (1994)
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