Aberrant sprouting of granule cell axons (mossy fibers) into the inner molecular layer of the dentate gyrus was first described nearly 40 years ago in lesion studies designed to evaluate reactive synaptogenesis. Later, mossy fiber sprouting was discovered in patients with temporal lobe epilepsy. The cause/effect relationship between mossy fiber sprouting and epileptogenesis is unclear and controversial. Some propose it creates a positive-feedback seizure-generating circuit. Others argue that sprouted mossy fibers preferentially excite inhibitory interneurons, thereby controlling seizure activity. This chapter reviews the literature on mossy fiber sprouting with respect to the following questions: Under what circumstances does it occur? How does it develop? And, what are the functional consequences?

UNDER WHAT CIRCUMSTANCES DOES MOSSY FIBER SPROUTING OCCUR?

Granule cell axons (mossy fibers) project into the dentate hilus and stratum lucidum of CA3 in rodents¹ and other species, including humans.² Mossy fibers synapse with inhibitory interneurons, hilar mossy cells, and CA3 pyramidal cells,³ but only very rarely with other granule cells (see below). Consequently, most granule cells normally do not display functional, monosynaptic, recurrent excitation.⁴ A minor mossy fiber projection into the granule cell layer can be visualized with the Timm stain, which generates opaque, silver particles specifically within zinc-rich mossy fiber boutons.⁵ At all septotemporal levels of the hippocampus, occasional scattered dendrites and cell bodies of interneurons in the granule cell layer are outlined by Timm-positive punctae,⁶ which electron microscopy has identified as mossy fiber synaptic boutons.⁷ This pattern of Timm staining in the granule cell layer appears to increase with age.⁸ At the temporal pole of the hippocampus, Timm staining reveals mossy fiber projections into the inner molecular layer that target granule cell dendrites.⁵ This minor, recurrent, excitatory pathway also increases with age.^9–12 The more extensive epilepsy-related recurrent mossy fiber pathway is an expansion of the normal, minimal circuit already present.¹³

Aberrantly high levels of mossy fiber sprouting were first discovered during experiments investigating lesion-induced changes in neuronal connectivity. After transection of perforant path input to the dentate gyrus in young rats, black Timm staining was detected in the inner molecular layer.¹⁴ More extensive and consistent mossy fiber sprouting developed after lesioning commissural/associational input to the inner molecular layer.⁶ Electron microscopy revealed that lesion-induced sprouted mossy fibers synapse with granule cell dendrites.^6,15

Mossy fiber sprouting was first found in patients with temporal lobe epilepsy by Scheibel et al.¹⁶ who reported Golgi-stained mossy fibers project from the hilus, through the granule cell layer, and into the molecular layer, where their boutons appose granule cell dendrites. Later, Nadler et al.¹⁷ discovered extensive mossy fiber sprouting in rats that had been treated one month earlier with the excitotoxant kainic acid. Figure 1 shows mossy fiber sprouting in epileptic pilocarpine-treated rats. Perhaps because of the technical challenges of using the Golgi stain to follow individual granule cell axons, mossy fiber sprouting in human epileptic tissue was initially reported as rare (< 1% of granule cells).¹⁶ However, later studies used Timm staining and dynorphin-immunoreactivity as markers for mossy fibers and found substantial sprouting in patients with mesial temporal lobe epilepsy.^10,18–20 Subsequently, mossy fiber sprouting was discovered in many different epilepsy-related conditions and some non-epileptic conditions (Table 1).

Figure 1

Mossy fiber sprouting in epileptic pilocarpine-treated rats. A1 Timm staining of the dentate gyrus (h=hilus, g=granule cell layer, m=molecular layer) and CA3 region. A2 Magnified view of boxed region in A1 shows a dense band of black Timm-staining in (more...)

Table 1

Conditions in which mossy fiber sprouting occurs in the dentate gyrus (early references indicated).

Temporal lobe epilepsy, the condition most frequently associated with mossy fiber sprouting, is the most common type of epilepsy in adults.²¹ Some patients have a lesion (a hamartoma or glioma, for example) in their temporal lobe, but most have mesial temporal lobe epilepsy, which typically involves extensive neuron loss especially in the hippocampus and in at least some cases a history of a precipitating injury.^22,23 Although robust mossy fiber sprouting is a common pathological finding in patients with mesial temporal lobe epilepsy,^24,25 there are exceptions.^26,27 Lynd-Balta et al.²⁸ proposed young children with mesial temporal lobe epilepsy develop mossy fiber sprouting long after other changes, including neuron loss and altered expression of glutamate receptors. However, other investigators found mossy fiber sprouting similar to that of adult patients in children as young as 5.5 months old.²⁹ Mossy fiber sprouting does not occur exclusively in patients with mesial temporal lobe epilepsy. It also occurs in children secondary to cortical dysplasias without obvious hippocampal damage.³⁰ In those cases, however, the amount of sprouting is less than in children with hippocampal seizures.^29,31 On average, adult patients with mesial temporal lobe epilepsy have more mossy fiber sprouting than those with lesion-related temporal lobe epilepsy, but there is overlap between groups.²⁵ Mossy fiber sprouting can occur in epileptic patients without mesial temporal lobe epilepsy.³² And, mild mossy fiber sprouting has been reported in patients with bipolar disorder but not epilepsy.³³ To better understand the circumstances that result in mossy fiber sprouting, it helps to consider the molecular and cellular mechanisms underlying its development.

HOW DOES MOSSY FIBER SPROUTING DEVELOP?

Mechanisms underlying mossy fiber sprouting remain unclear, but available evidence suggests likely triggers. One is seizure activity, which appears capable of causing mild mossy fiber sprouting without obvious neuron loss.^34–39 However, seizure activity alone is not always sufficient, because many seizures can propagate through the dentate gyrus without causing mossy fiber sprouting, as in Mongolian gerbils with inherited epilepsy.^7,40 Intense mossy fiber sprouting, like that found in patients with mesial temporal lobe epilepsy, appears to require deafferentation of granule cells either by transecting axons⁶ or killing presynaptic neurons.^17,41,42 Hilar mossy cells give rise to the associational pathway of the dentate gyrus (and in rodents, the commissural pathway),^43,44 account for ~60% of all hilar neurons,^45–47 and synapse with granule cell dendrites in the inner molecular layer,⁴⁸ which also are the primary target of sprouted mossy fibers. Extent of mossy fiber sprouting correlates with hilar neuron loss in patients with mesial temporal lobe epilepsy^19,20,26 and in laboratory animal models.^49–52 More specifically, mossy cell loss correlates with mossy fiber sprouting in epileptic pilocarpine-treated rats.⁴⁷ However, fundamental questions persist. Is mossy cell loss alone sufficient to cause mossy fiber sprouting?⁵³ What is it about mossy cell loss that facilitates mossy fiber sprouting: granule cell deafferentation, removal of a synaptic target of mossy fibers, or both?⁵⁴ Complicating the issue, the most common experimental method used to produce mossy fiber sprouting is status epilepticus, which involves many other potential triggers in addition to mossy cell loss.

Whatever the events are that trigger mossy fiber sprouting, presumably they are transduced to granule cells as molecular cues that activate signaling pathways to coordinate mossy fiber growth and synaptogenesis. c-Fos was proposed as an early step in the process.³⁵ However, increased expression of c-fos and some other immediate early genes do not appear necessary for mossy fiber sprouting.^55,56 Increased expression of GAP-43, a membrane-bound protein concentrated at growth cones and developing presynaptic terminals, was proposed to promote mossy fiber sprouting.^24,57–60 In addition to GAP-43, tubulins⁶¹ and microtubule-associated proteins⁶² could be involved in mossy fiber sprouting. However, in regard to the molecular mechanisms underlying mossy fiber sprouting, BDNF has received the most attention. BDNF expression increases in the dentate gyrus after seizures.^63,64 BDNF promotes granule cell hypertrophy⁶⁵ and mossy fiber branching.⁶⁶ When infused in control animals, BDNF causes seizure activity and mild mossy fiber sprouting.⁶⁷ And, electroconvulsive seizure-induced sprouting is diminished in BDNF heterozygote knockout mice.³⁸ In contrast, other reports challenge the role of BDNF in mossy fiber sprouting. Mild mossy fiber sprouting develops in slice cultures from homozygote BDNF knockout mice⁶⁸ and after kindling in heterozygote BDNF knockout mice.⁶⁹ Transgenic overexpression of BDNF does not cause mossy fiber sprouting.⁷⁰ The timing of BDNF expression relative to development of mossy fiber sprouting has been questioned.⁷¹ And, Vaidya et al.³⁸ reported that BDNF infusion does not cause mossy fiber sprouting. Nevertheless, strong evidence comes from organotypic culture experiments that induced mossy fiber sprouting by application of BDNF or a GABA_A receptor antagonist.⁷² In those experiments, an L-type calcium channel blocker, sodium channel blocker, TrkB inhibitor, function-blocking anti-BDNF antibody, and transfection with dominant-negative TrkB each reduced mossy fiber sprouting. Thus, it seems likely that BDNF plays a role in mossy fiber sprouting but specific signaling pathways and molecular targets remain unclear.

The laminar specificity of sprouted mossy fibers is remarkable. For example, in most hippocampal slice cultures the outer molecular layer is almost completely denervated but is relatively unstained for mossy fibers, which remain confined to the inner molecular layer.⁴² Such specificity suggests strong attractant and/or repulsive extracellular signals. Although several molecular candidates have been proposed – including NCAMs,^73,74 tenascin-C,⁷⁵ Sema3A,⁷⁶ and hyaluronan⁷⁷ – none can fully account for precise targeting by sprouted mossy fibers, which remains an important area for research. In summary, there still is much to learn about the molecular mechanisms involved in transducing triggering stimuli, coordinating mossy fiber growth, and directing mossy fibers to their synaptic targets.

At the cellular level, an increasingly detailed picture of mossy fiber sprouting has emerged. After status epilepticus in rats, ~3 months are required for mossy fiber sprouting to fully develop.^12,78,79 Once fully developed, the proportion of granule cells with sprouted mossy fibers appears to be ~60% in patients with mesial temporal lobe epilepsy⁸⁰ and laboratory animal models,^81–84 but more precise estimates are needed. Recent findings suggest only new adult-generated granule cells sprout mossy fibers into the molecular layer. Granule cell neurogenesis normally continues throughout life. For example, in young adult control rats the number of new granule cells generated each month is 6% of the total population.⁸⁵ Granule cell neurogenesis accelerates after status epilepticus⁸⁶ or even milder seizure activity.⁸⁷ Although earlier studies questioned the role of newborn granule cells in mossy fiber sprouting,^88,89 later work showed that granule cells born up to 4 weeks before status epilepticus⁹⁰ and up to 4 days after can develop aberrant mossy fiber projections to the inner molecular layer, whereas older granule cells (born ≥ 7 weeks before status epilepticus) do not.⁹¹ Identification of newborn granule cells as the source of aberrant mossy fibers is an important advance in our understanding of how mossy fiber sprouting develops, but questions persist. Why do newborn granule cells develop aberrant connections? Are the underlying causes attributable to intrinsic, perhaps epigenetic, changes in granule cells, to extrinsic cues in the microenvironment, or to both? Are underlying causes transient or permanent - and if permanent, can they be reversed? Do all newborn granule cells form aberrant connections or just a subset? And, how long following a precipitating injury will newborn granule cells continue to develop aberrant connections?

Human epileptic tissue displays evidence of ongoing synaptic reorganization years after precipitating injuries and the onset of spontaneous seizures.^24,74,80 Although these results might suggest mossy fiber sprouting continually progresses and becomes increasingly more severe with time, in laboratory animal models, which can be evaluated more extensively and with more temporal resolution, levels of mossy fiber sprouting appear to plateau after 3 months.¹² Together, these findings and the neurogenesis data described above suggest older, sprouted mossy fibers might be replaced by new ones. If aberrant circuits continually turnover, there may be opportunities to interrupt the pathophysiological process even after robust mossy fiber sprouting develops. Consistent with this notion, after a 45 day delay, during which time some sprouting is likely to have developed, grafts of CA3 pyramidal neurons reduce mossy fiber sprouting following kainate-infusion.⁷⁹ Furthermore, levels of mild mossy fiber sprouting after experimental electroconvulsive treatment peak and then decrease at later time points, suggesting at least partial reversal.³⁸ Therefore, despite evidence that mossy fiber sprouting is long-lasting or even permanent,^32,78,92 it might be worthwhile to further test its stability.

At the microcircuit level, in vivo spatial features of mossy fiber sprouting have been evaluated using axon tracers⁸¹ and intracellular labeling.⁸² Individual granule cells extend mossy fibers into the inner molecular layer over an area with an average radius of 600 μm, which is comparable to the span of hilar collateral projections in control animals. Plotting the corresponding area onto a calibrated, flattened map of the rat dentate gyrus,⁹³ and using an estimate of 1 million granule cells per rat dentate gyrus,⁹⁴ one can predict that ~42,000 granule cells are within reach of one granule cell’s sprouted mossy fibers. Integrating axon-length-per-cell with synapse-density-per-axon-length suggests each granule cell that sprouts mossy fibers into the molecular layer forms an average of ~500 new synapses with other granule cells.⁹⁵ If one assumes that each new synapse is with a different granule cell and ~60% of granule cells in epileptic rats sprout mossy fibers, then the probability of finding a monosynaptically coupled granule cell within another cell’s reach is 0.7% - which is consistent with experimental results.⁹⁶ In addition to mossy fiber projections into the inner molecular layer, granule cells in epileptic animals have greater axon length in the hilus,⁸² increased branching of hilar collaterals,⁸³ and more boutons in the hilus.⁸¹ In the hilus of epileptic animals, therefore, mossy fibers might hyperinnervate surviving neurons, consistent with recent findings from recordings of hilar somatostatin interneurons.⁹⁷ Epilepsy-related mossy fiber sprouting also occurs in stratum oriens of CA3,⁹⁸ but the present review focuses on the dentate gyrus.

In addition to their normal synaptic targets, in epileptic tissue sprouted mossy fibers form asymmetric (excitatory) synapses with ectopic granule cells in the hilus,^99,100 with granule cell basal dendrites in the hilus,^101,102 with granule cell somata in the granule cell layer,^83,103 and with granule cell apical dendrites in the granule cell layer and inner molecular layer^{12,20,101,104–106} (including occasional autapses^83,101). In the inner molecular layer, ~90% of mossy fiber synapses are with dendritic spines, the remainder with dendritic shafts. Mossy fiber synapses with granule cells are abundant, accounting for ~50% of all inner molecular synapses in epileptic pilocarpine-treated rats.^94,100 Compared to other excitatory synapses in the inner molecular layer, mossy fiber synapses appear to be larger and are more likely to be perforated,^94,105 features that suggest greater synaptic strength.^107,108 Overall, there is considerable anatomical evidence that mossy fiber sprouting creates a positive-feedback circuit among granule cells.

Sprouted mossy fibers also synapse with inhibitory interneurons but much less frequently than with granule cells.^83,105 Some have proposed that sprouted mossy fibers hyperinnervate parvalbumin-immunoreactive basket cells.^109,110 Others have countered that even in control tissue those interneurons receive high levels of mossy fiber input.¹¹¹ If interneurons were hyperinnervated by excitatory synapses after mossy fiber sprouting, one would predict the frequency of spontaneous inhibitory postsynaptic currents in granule cells to be more sensitive to glutamatergic receptor antagonists, which was reported.¹¹² However, one also would expect that miniature excitatory postsynaptic current frequency in basket cells – a more direct measure of the number of glutamatergic synapses impinging upon basket cells – would increase as mossy fiber sprouting develops; however, it does not.¹¹³ In vivo biocytin-labeling and 3-dimensional reconstruction of serial electron micrographs of sprouted mossy fibers revealed only ~5% of synapses formed by sprouted mossy fibers in the granule cell layer and molecular layer are with GABA-immunoreactive neurons, the other ~95% are with granule cells.⁹⁵ Integrating synaptic density, synaptic target frequency, and sprouted mossy fiber length, these findings suggest the average granule cell with sprouted mossy fiber collaterals forms 20 times more new synapses with granule cells than with interneurons.

WHAT ARE THE FUNCTIONAL CONSEQUENCES OF MOSSY FIBER SPROUTING?

As expected from anatomical evidence reviewed above, mossy fiber sprouting creates an aberrant, recurrent, excitatory circuit. Functional positive-feedback among granule cells has been demonstrated with varying experimental approaches and degrees of confidence. In animals with mossy fiber sprouting, but not in controls, in vivo perforant path stimulation evokes a delayed current sink in the inner molecular layer¹¹⁴ and reverberating field potential responses, which are consistent with positive-feedback among granule cells.^50,82,115 As in hippocampal slice studies,¹¹⁶ reverberating responses in vivo become most apparent after inhibition is blocked. A limitation of the in vivo approach, however, is that perforant path stimulation activates many circuits in addition to sprouted mossy fibers. In hippocampal slices, especially with GABA_A receptors at least partially blocked or extracellular potassium ion concentration elevated, antidromic stimulation of mossy fibers evokes depolarizing synaptic responses in granule cells more frequently after sprouting, consistent with the formation of recurrent, excitatory connections.^{13,26,116–119} However, even with more focal electrical stimulation in hippocampal slice experiments compared to in vivo studies, axons other than sprouted mossy fibers could be activated, including projections from mossy cells and CA3 pyramidal cells. More specific activation of granule cells with glutamate uncaging or glutamate microdrop application evokes synaptic responses in other granule cells more frequently in slices with mossy fiber sprouting compared to controls.^120–123 Although unlikely, the possibility of polysynaptic activation through surviving mossy cells and CA3 pyramidal cells cannot be excluded completely, even with these methods. Scharfman et al.⁹⁶ provided the strongest evidence to date that mossy fiber sprouting creates a functional positive-feedback circuit among granule cells. In hippocampal slices from epileptic pilocarpine-treated rats with sprouting, but not in controls, granule cells generate monosynaptic excitatory potentials in other granule cells. The probability of monosynaptic coupling between granule cells after sprouting is 0.66%,⁹⁶ which is similar to estimates based on anatomical data (see above) and a level approaching that normally found among CA3 pyramidal cells.¹²⁴ The average amplitude of granule cell-to-granule cell synaptic responses is ~2 mV, and their failure rate is 60–70%,^96,122,125 which is not unusual for excitatory synapses in cortical areas. Granule cell-to-granule cell synapses utilize AMPA/KA- and to a smaller extent NMDA-receptors.^13,122 Kainate-receptors account for an unusually large amount of charge transfer at mossy fiber synapses with granule cells.¹²⁶ Granule cell-to-granule cell synapses can be presynaptically blocked by type II metabotropic glutamate receptors, presynaptically facilitated by kainate-receptors, and they display frequency-dependent short-term plasticity intermediate of that of normal mossy fiber synapses with interneurons and CA3 pyramidal cells.¹²⁵

Thus, both anatomical and functional evidence confirms that after mossy fiber sprouting, granule cells receive abnormally high levels of synaptic input from other granule cells, which is minimal in control animals. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) in granule cells increases with mossy fiber sprouting,^121,127 which could be attributable to more excitatory synapses. However, another possibility is increased levels of activity in slices from epileptic animals. Consistent with the latter possibility, the frequency of miniature EPSCs - which depends on numbers of synapses and probability of release but not action potentials - is similar in granule cells before and after mossy fiber sprouting,¹²⁶ not increased as would be expected if granule cells were to receive more synapses after sprouting. A stereological, electron microscopy study estimated numbers of excitatory synapses with proximal dendrites per granule cell in control rats, in rats 5 days after status epilepticus, and in chronically epileptic animals.⁹⁴ Shortly after status epilepticus, which kills many hilar mossy cells, the number of synapses is reduced to < 40% of control levels, but weeks later recovers to ~85% of controls. Sprouted mossy fibers are likely to account for much, if not all, of the recovery. Together, these findings suggest mossy fiber sprouting nearly replaces but does not exceed the original number of inner molecular layer glutamatergic synapses lost by granule cells during precipitating injuries.

The cellular electrophysiological evidence reviewed above demonstrates effects of mossy fiber sprouting at the synaptic level. However, the most important question about mossy fiber sprouting from a clinical standpoint is whether it is epileptogenic, compensatory, or neither. The extensive literature on this topic will be reviewed beginning with relevant hypotheses. Shortly after it was discovered in kainate-treated rats, Tauck and Nadler¹¹⁷ proposed mossy fiber sprouting creates an aberrant positive-feedback network among granule cells that synchronizes their activity and facilitates seizure activity. After many years of accumulating data, Nadler restated the hypothesis and added that “the recurrent mossy fiber pathway promotes seizure propagation from the entorhinal cortex to the hippocampus mainly when granule cells are driven at a frequency appropriate to promote synaptic facilitation” [≥1 Hz].¹²⁵ Buhl et al.¹¹² suggested that sprouted mossy fibers contribute to seizures during periods of high activity but through a different mechanism. They proposed that changes in subunit expression of GABA_A receptors on granule cells in epileptic animals makes them vulnerable to negative modulation by zinc. Further, they proposed that during periods of intense activity, granule cells synaptically release zinc from sprouted mossy fibers, which diffuses to GABAergic synapses and reduces inhibition when it is critically needed. Thus, two hypotheses (recurrent excitation and zinc-induced collapse of inhibition) contend that mossy fiber sprouting is epileptogenic. In contrast, Sloviter¹²⁸ proposed sprouted mossy fibers preferentially synapse with basket cells and restore powerful recurrent inhibition lost after injuries kill hilar mossy cells. Recently, Sloviter et al.¹¹⁰ restated the view that “mossy fiber sprouting may play a clinically important role in retarding seizure spread (keeping subclinical seizures subclinical).” Simmons et al.¹²⁷ proposed that effects of mossy fiber sprouting are mixed. Some of their data support the recurrent excitation hypothesis, but they also proposed sprouted mossy fibers release opioid peptides that have anticonvulsant effects. Other inhibitory transmitters that could be released by sprouted mossy fibers include NPY¹²⁹ and GABA.¹³⁰ Finally, Gloor¹³¹ reviewed the literature on neuron loss in temporal lobe epilepsy, considered evidence of synaptic reorganization, and suggested that mossy fiber sprouting might be an epiphenomenon with neither pro- or anti-epileptic effects. Investigators have worked within the context of these diverging hypotheses. For purposes of review, reports on functional consequences of mossy fiber sprouting are summarized below in three categories: kindling studies, experiments that evaluated evoked seizure-like events, and investigations that measured frequencies of spontaneous seizures in patients with temporal lobe epilepsy and laboratory animal models.

In early kindling studies, hyperexcitability and mossy fiber sprouting were shown to develop in parallel, suggesting sprouting might be epileptogenic.^34,92 Later studies revealed that hyperexcitability and mossy fiber sprouting can be dissociated.^132,133 But in a broader sense, implications of kindling studies for the role of mossy fiber sprouting in temporal lobe epileptogenesis might be limited. Animals do not display spontaneous seizures unless kindled very extensively - for example, ~100 times in rats.¹³⁴ More typical kindling paradigms that involve only 10–20 stimulations generate levels of mossy fiber sprouting far below that found in many patients with mesial temporal lobe epilepsy and other laboratory animal models.⁴¹ Instead, kindling might more closely model the mild mossy fiber sprouting found with experimental conditions that kill few, if any, neurons and the mild mossy fiber sprouting found in some patients in which hippocampal neurons are largely spared. This mild form of mossy fiber sprouting might be an effect, not a cause, of seizure activity.

Another set of studies tested whether evoked seizure-like responses correlate with extent of mossy fiber sprouting. Simulations run on a computer model of dentate circuitry suggested mossy fiber sprouting has little effect on granule cell activity and attributed the lack of effect to the granule cells’ stabilizing intrinsic physiological properties.¹³⁵ However, later, more realistic computer models found mossy fiber sprouting promotes spread of seizure-like activity.¹³⁶ A strength of the in silico approach is the ability to specifically test individual parameters while leaving other conditions unchanged; these studies showed that mossy fiber sprouting alone is sufficient to cause hyperexcitability in the modeled dentate gyrus.¹³⁷ Furthermore, incorporating a small number of highly interconnected granule cells greatly increases network activity.¹³⁸ Whether granule cell network hubs actually exist in epileptic tissue and generate seizures is an intriguing prediction to be tested in future experiments. In addition to computer models, actual epileptic tissue has been evaluated. In organotypic slice cultures, kainate treatment causes mossy fiber sprouting but does not affect seizure activity.¹³⁹ In contrast, in experiments with acute slices, evoked seizure-like responses by granule cells are more likely after mossy fiber sprouting develops in patients with mesial temporal lobe epilepsy¹⁴⁰ and in rodent models.^{120,121,141,142} In summary, much, but not all, computer modeling and experimental slice data are consistent with the hypothesis that mossy fiber sprouting is epileptogenic. Compared to in vivo experiments, these studies reduced confounding influences from outside structures and more specifically evaluated the dentate gyrus region where sprouting occurs. However, caveats include the unclear relevance of computer models and hippocampal slice preparations to in vivo situations, the common requirement for pro-convulsant conditions (for example GABA_A receptor antagonists and elevated potassium ion concentrations) to unmask seizure-like responses, and dependency on provoking stimuli, which is unlike typically unprovoked seizures in patients.

Spontaneous seizures can be measured in vivo and compared with extent of mossy fiber sprouting in laboratory animal models and when tissue is surgically resected to treat patients. Some studies found correlations between the extent of mossy fiber sprouting and seizure frequency,^{41,83,143–146} but many have not.^{26,28,50–52,54,78,128,147–158} Thus, although a loose association between the development of epilepsy and moderate-to-intense levels of mossy fiber sprouting is commonly reported (in other words, epileptic animals are more likely to display mossy fiber sprouting than non-epileptic individuals), consistently replicable, statistically significant correlations between seizure frequency and mossy fiber sprouting are lacking. Most in vivo evidence listed above, therefore, supports the hypothesis that mossy fiber sprouting might be an epiphenomenon without major pro- or anti-epileptic effects. However, seizure monitoring methods used by many previous experiments suffered from limited sampling and might have been statistically under-powered, which increases variability in seizure frequency data, making it more difficult to detect subtle correlations. Another potential source of variability are myriad other parameters that might change independently of mossy fiber sprouting and have confounding effects on seizure frequency. Ideally, to more rigorously test its role in epileptogenesis, one would like to specifically block only the development of mossy fiber sprouting after an epileptogenic injury, carefully monitor the frequency and severity of spontaneous seizures, and compare the results to a similarly treated group in which mossy fiber sprouting developed.

Most efforts to block mossy fiber sprouting have been unsuccessful, despite testing reasonable candidate mechanisms. One prior attempt neutralized nerve growth factor with antibodies, which suppressed sprouting by cholinergic axons but not mossy fibers.¹⁵⁹ Treatment with the anticonvulsant vigabatrin did not block mossy fiber sprouting when administered to rats after kainate-induced status epilepticus.¹⁶⁰ Blocking neural activity by continuously infusing tetrodotoxin into the dentate gyrus for a month after status epilepticus did not suppress mossy fiber sprouting and might have made it worse.¹⁶¹ It was reported that blocking protein synthesis with cycloheximide around the time of epileptogenic injury reduced mossy fiber sprouting.^53,162,163 However, cycloheximide pretreatment reduces excitotoxic damage during status epilepticus;^87,89,164 therefore, mossy fiber sprouting may have been reduced indirectly by reducing hilar neuron loss.¹⁶⁵ Furthermore, when administered systemically as in the original experiments¹⁶⁶ or infused directly into the dentate gyrus¹⁶⁷ cycloheximide’s effect on mossy fiber sprouting could not be reproduced by other investigators. Therefore, it is doubtful that transiently blocking protein synthesis directly prevents mossy fiber sprouting.

Mossy fiber sprouting presumably begins with formation of growth cones, and previous attempts targeted growth cone function by blocking L-type calcium channels and inhibiting the calcium-activated phosphatase, calcineurin. Systemic administration of the L-type calcium channel blocker nicardipine was reported to suppress mossy fiber sprouting after pilocarpine-induced status epilepticus.¹⁶⁸ And, the calcineurin inhibitor FK506 was reported to inhibit kindling¹⁶⁹ and block mossy fiber sprouting.¹⁷⁰ However, after a month of continuous, direct infusion into the dentate gyrus of nicardipine, FK506, or cyclosporin A (another calcineurin inhibitor), extent of mossy fiber sprouting was similar in infused versus noninfused hippocampi of rats that had experienced status epilepticus.¹⁷¹

The ketogenic diet was reported to reduce mossy fiber sprouting after kainate-induced status epilepticus,¹⁷² but sample sizes in that study were small and results should be verified. Chronic treatment with oral lithium at therapeutically relevant concentrations was reported to suppress mossy fiber sprouting after pilocarpine-induced status epilepticus.¹⁷³ However, in that study, status epilepticus was curtailed early, and the level of excitotoxicity appeared insufficient to produce an adequate baseline level of mossy fiber sprouting for comparison. The NR2B-selective NMDA antagonist (Ro 25,6981) suppressed mossy fiber sprouting in organotypic cultures,¹⁷⁴ but it is unclear whether it would be effective in vivo. Grafting embryonic CA3 pyramidal cells into the hippocampus reduces mossy fiber sprouting after kainate-induced status epilepticus,⁷⁹ but grafted neurons sprout axons into the inner molecular layer of the dentate gyrus, suggesting they might suppress development of one recurrent excitatory circuit (among granule cells) by establishing another aberrant positive-feedback circuit in its place (a disynaptic circuit between CA3 pyramidal cells and granule cells).

Recently, a new treatment was discovered that suppresses mossy fiber sprouting. Rapamycin administered systemically¹⁷⁵ or directly infused into the dentate gyrus¹⁷⁶ reduces mossy fiber sprouting after chemoconvulsant-induced status epilepticus in rats. Rapamycin inhibits the mTOR signaling pathway that transduces extracellular signals, including BDNF, to control protein synthesis and cell growth.^177,178 Systemic treatment with rapamycin was reported to suppress both mossy fiber sprouting and seizure frequency in rats.¹⁷⁵ In pilocarpine-treated mice, however, systemic rapamycin suppressed mossy fiber sprouting but did not affect seizure frequency.¹⁷⁹ Possible explanations for the apparently contradictory results include a confounding anticonvulsant effect of rapamycin specifically in rats.¹⁸⁰ In conclusion, the role of mossy fiber sprouting in epileptogenesis remains unclear. As additional methods are discovered to block its development selectively, more opportunities will arise to test its functional effects. In addition to granule cells, epilepsy-related axon reorganization occurs among other excitatory neurons, including CA3 pyramidal cells,^181,182 CA1 pyramidal cells,¹⁸³ subicular neurons,¹⁵² and neocortical neurons.¹⁸⁴ Therefore, future lessons learned from continued study of mossy fiber sprouting might have more general relevance for a broad range of patients with epilepsy and other brain disorders that involve synaptic reorganization.

Acknowledgments

The author’s work is supported by NIH-NINDS.

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