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Single Mossy Fiber Axonal Systems of Human Dentate Granule Cells Studied in Hippocampal Slices from Patients with Temporal Lobe Epilepsy

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Single Mossy Fiber Axonal Systems of Human Dentate Granule Cells Studied in Hippocampal Slices from Patients with Temporal Lobe Epilepsy The Journal of Neuroscience, April 1993, f3(4): 151 l-l 522 Single Mossy Fiber Axonal Systems of Human Dentate Granule Cells Studied in Hippocampal Slices from Patients with Temporal Lobe Epilepsy Masako Isokawa,’ Michel F. Levesque,2 Thomas L. Babb,ls and Jerome Engel, Jr.lv3 ‘Brain Research Institute and Departments of ‘Neurosurgery and 3Neurology, School of Medicine, University of California, Los Angeles, California 90024-1761 Previous histological and immunocytochemical studies sug- present findings are epilepsy associated. However, the pres- gest that reorganization of the dentate granule cell axons, ence of aberrant mossy fiber collaterals in the hippocampi the mossy fibers, can occur in epileptic human hippocampus used in the present study has been confirmed by Timm’s (Sutula et al., 1989; Houser et al., 1990; Babb et al., 1991) staining and/or dynorphin immunohistochemistry in com- and in animal models of epilepsy (Tauck and Nadler, 1985; parison with nonepileptic autopsy material, indicating its re- Sutula et al., 1988; Cronin et al., 1992). However, neuroan- lation to epilepsy (Babb et al., 1991, 1992). At present, there atomical analyses of the trajectory and morphology of re- seems to be a consensus that the projection of mossy fiber organized axons are not yet available. The present study collaterals to the supragranular layer is a rare occurrence in was conducted to investigate single dentate granule cell normal rats (Lorento de No, 1934; Claiborne et al., 1988; axonal systems in human epileptic hippocampus. Individual Seress et al., 1991; present study), normal monkeys (Seress mossy fibers were directly visualized by injecting a tracer et al., 1991), and normal humans (Houser et al., 1990). Thus, (biocytin or Lucifer yellow) intracellularly in hippocampal we believe that the intracellularly stained aberrant axon col- slices prepared from temporal lobes that were surgically laterals reported here in the supragranular layer likely rep- removed from patients for treatment of intractable epilepsy. resent trajectories of reorganized mossy fibers associated Two major arborization patterns were identified: (1) the par- with medically intractable temporal lobe epilepsy. ent axons extended to and coursed through the hilus toward [Key words: intracellular injections, granule cell axons, CA3, leaving collaterals along their paths in the hilus (N = biocytin, Lucifer yellow, sprouting, filopodia] 19 neurons); (2) in addition to the aforementioned axonal system, collateral(s) branched from the parent axon near the soma and projected to the granule cell layer and molecular Recent histological and immunocytochemical studies on epi- layer, forming an aberrant axonal pathway (N = 9 neurons). leptic human hippocampussuggest that the dentate granule cell These aberrant collaterals bore large boutons similar to those axons, the mossy fibers, in epileptic hippocampus have a col- of the hilar axons and formed extensive plexuses in the lateral arborization pattern that is different from that of normal granule cell layer and/or in the molecular layer. The summed mossy fibers in lower mammalsand in autopsy control human length of collaterals in the granular/molecular layers was tissues(Sutula et al., 1989; Houser et al., 1990; Babb et al., 1110.8 Frn on average, which was one-fourth of the total 1991). These aberrant collaterals were localized by Timm’s summed length of the mossy fibers (3898.5 pm on average). staining or dynorphin immunoreactivity as a band of reaction The size of the somata in neurons that had aberrant collat- product in the supragranularregion, especiallyin the inner mo- erals was significantly larger than that of neurons without lecular layer of the dentate gyrus. Becausethe mossy fibers nor- such collaterals (p < 0.025). In four cases, filopodium-like mally extend their arbors to the polymorph (hilar) region of the fine processes were present near the axon hillock and prox- dentate gyrus and CA3 field of the hippocampusproper, but do imal parts of the parent axon, suggesting that the aberrant not project to the molecular layer (Lorento de N6, 1934; Clai- collateral formation might be an ongoing process in these borne et al., 1986),epileptogenic dentate granule cellshave been tissues. The lack of control slices from normal living human thought to sprout axon collaterals beyond their normal arbo- hippocampus makes it difficult to assess to what extent the rization domain. The intensity of this sprouting showeda pos- itive correlation to the severity of seizure activities (Sutula et al., 1989) and the severity of hilar cell loss(Houser et al., 1990). Received June 9, 1992; revised Oct. 6, 1992; accepted Oct. 12, 1992. We thank Dr. F. E. Dudek for his assistance in settine uo our brain slice svstem. This finding in human epileptic hippocampuswas supportedby Dr. R. S. Fisher for letting us use his fluorescent micro&&e, Dr. D. M. Finch for several animal models of epilepsy. The kainate model (Tauck helpful comments and editorial assistance, and the members of the Clinical Neu- and Nadler, 1985), the kindling model (Sutula et al., 1988), and rophysiology Project for their clinical expertise. This research was conducted with permission of the UCLA Human Subjects Protection Committee and in accor- the pilocarpine model (Mello et al., 1990), all showeda dense dance with the guidelines of the Declaration of Helsinki. This work was supported band of Timm’s staining in the inner molecular layer, which bv NIH Grant NS02808. was indicative of reorganized mossy fiber paths. Physiological ~Correspondence should be addressed to Masako Isokawa, Ph.D., Brain Research Institute, CHS, UCLA, Los Angeles, CA 90024- 176 1. studiesin the kainate model suggestedthat sproutedfibers could Copyright 0 1993 Society for Neuroscience 0270-6474/93/13151 l-12$05.00/0 form recurrent excitatory circuits, constituting a possiblesub- 1512 lsokawa et al. * Single Mossy Fiber Axonal Systems in TLE Humans strate of epileptogenicity (Tauck and Nadler, 1985; Cronin et Materials and Methods al., 1992). However, cellular anatomy to elucidate the paths and Patient selection. Hippocampalslices were obtainedfrom 23 patients morphology of the sprouted fibers has not been reported in either who had medicallyintractable temporal lobe epilepsy and enteredthe human epileptic hippocampus or experimental models of epi- epilepsysurgery program for treatmentof their seizuredisorders. In all of them,there was evidence of a medialtemporal origin of epileptogenic lepsy. discharges.Patient selectionwas based on a seriesof evaluationsthat In the present study, we used a method of intracellular injec- includedEEG monitoring,neurological and cognitivetesting, positron tion of tracers (biocytin or Lucifer yellow) into living single emissiontomography, magnetic resonance imaging, and depth electrode dentate granule cells in human epileptic hippocampus main- implants(Engel, 1987). Neuroanatomical examinations ofthe surgically tained in vitro, and directly visualized their axonal morphology removedspecimens included cell countsto assessneuronal death and hippocampalsclerosis in epileptogenicregions (Babb et al., 1984).All and arborization patterns. The advantage of using this method of thesewere performedon every hippocampalspecimen as part of is (1) only a single neuron is stained at any one time per slice, routine examinationsfor the identificationof epilepticfocal pathology. so that all fibers visualized can be consideredto originate in the The resultsof pathologicalexaminations were made available from the stained neuron. This overcomes the disadvantageof using the data baseof the UCLA EpilepsySurgery Program. Brain tissues. The hippocampaltissue for slicepreparation was ob- Golgi staining, which stains multiple neurons simultaneously tained directly from neurosurgeonsat the University of Californiaat and yet capriciously stains only a subpopulation of total fibers. LosAngeles. The resectedhippocampus was immediately immersed in (2) In caseswhere stained neurons have aberrant fibers, the oxygen-containingice-cold artnicial cerebrospinal fluid censistingof (in relationship between the parent axon in the hilus and the ab- mM) 124NaCl, 3 KCI, 2.4CaCI,. 26 NaHCO,.1.3 M&O,. 1.24NaH,PO,. errant collateralsin the molecular layer can be qualitatively and and.10 glucose, pH 7.4. Slices’werecut perpendicular-tothe ant&or- posterioraxis of the hippocampusat a thicknessof 500pm (Vibroslicer, quantitatively studied. (3) Injecting a tracer in living cells may World PrecisionInstruments), and placedon the rampof a liquid-gas minimize the possibility of obscuring fine axonal branchesthat interfacerecording chamber (Haas et al., 1979)at 34 + 1°C.As a control might occur in autopsy or biopsy tissuesprepared for patho- comparison,normal rat hippocampalslices were prepared (10 males, logical examinations. 150-200am: CharlesRiver). The dentategranule cells were iniected” with the sametracers and with the sameexperimental protocols using From the nature of this study, which usesliving human hip- our humanbrain slicechamber. This procedureprovided (1) technical pocampal specimens,our findings cannot be directly compared confirmationon intracellulardye filling in humanepileptic neurons and to normal controls that would be obtained from disease-free (2) a guidelinefor criteria in selectingneurons with satisfactorytracer living human hippocampus.Ethical considerationspreclude the injections. use of such tissue. In the present study, we made the following Intracellular injection of tracers. Either
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