Absence of hippocampal mossy fiber sprouting in transgenic mice overexpressing brain-derived neurotrophic factor

Excess neuronal activity upregulates the expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in adult hippocampus. Nerve growth factor has been shown to contribute the induction of aberrant hippocampal mossy fiber sprouting in the inner molecular layer of the dentate gyrus, however the role of prolonged brain-derived neurotrophic factor exposure is uncertain. We examined the distribution and plasticity of mossy fibers in transgenic mice with developmental overexpression of brain-derived neurotrophic factor. Despite 2--3-fold elevated BDNF levels in the hippocampus sufficient to increase the intensity of neuropeptide Y immunoreactivity in interneurons, no visible changes in mossy fiber Timm staining patterns were observed in the inner molecular layer of adult mutant hippocampus compared to wild-type mice. In addition, no changes of the mRNA expression of two growth-associated proteins, GAP-43 and SCG-10 were found. These data suggest that early and persistent elevations of brain-derived neurotrophic factor in granule cells are not sufficient to elicit this pattern of axonal plasticity in the hippocampus.     

Amygdala kindling develops without mossy fiber sprouting and hippocampal neuronal degeneration in rats

Repeated electrical stimulation of limbic structures has been reported to produce the kindling effect together with morphological changes in the hippocampus such as mossy fiber sprouting and/or neuronal loss. However, to argue against a causal role of these neuropathological changes in the development of kindling-associated seizures, we examined mossy fiber sprouting in amygdala (AM)-kindled rats using Timm histochemical staining, and evaluated the hippocampal neuronal degeneration in AM-kindled rats by terminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nick end labelling (TUNEL). Amygdala kindling was established by 10.3 +/- 0.7 electrical stimulations, and no increase in Timm granules (neuronal sprouting) was observed up to the time of acquisition of a fully kindled state. However, the density and distribution of Timm granules increased significantly in the dentate gyrus compared with unkindled rats after 29 after-discharges or more than 10 kindled convulsions. In addition, no significant increase in TUNEL-positive cells was found in the hilar polymorphic neurons or in CA3 pyramidal neurons of the kindled rats that had fewer than 29 after-discharges. However, a significant increase of TUNEL-positive cells was found in the granule cell layer in the dentate gyrus of the stimulated side after 18 after-discharges or 10 kindled convulsions. Our result show that AM kindling develops without evidence of mossy fiber sprouting, and that mossy fiber sprouting may appear after repeated kindled convulsions, following death of the granule cells in the dentate gyrus.     

The effects of fimbria/fornix transections on perforant path kindling and mossy fiber sprouting

Various clinical and experimental studies of epilepsy have described synaptic reorganization in the dentate gyrus of hippocampus, in the form of collateral sprouting of the mossy fibers. These reports have led to the hypothesis that reorganized mossy fibers form a functional excitatory feedback circuit that contributes to local circuit hyperexcitability and chronic seizures. Much of the evidence supporting the sprouting hypothesis has been derived from kindling. We recently reported that transection of the fimbria/fornix (FF), which produces chronic epileptiform activity in the hippocampus, also induces mossy fiber sprouting in the inner molecular layer of the dentate gyrus. In the present study, we attempted to determine whether mossy fiber sprouting contributes to epileptiform activity, by examining the effects FF transections on perforant path (PP) kindling and associated mossy fiber sprouting. We found that FF transections and PP kindling produced moderate levels of sprouting, whereas the combination of the two treatments produced significantly denser sprouting. FF transections had mixed effects on kindling: afterdischarge thresholds were decreased and clonus and afterdischarge durations were increased, suggesting increased local excitation, whereas the kindling of behavioral seizures was delayed, suggesting decreased epileptogenesis.     

Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats

The mossy fiber pathway in the dentate gyrus undergoes sprouting and synaptic reorganization in response to seizures. The types of new synapses, their location and number, and the identity of their postsynaptic targets determine the functional properties of the reorganized circuitry. The goal of this study was to characterize the types and proportions of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. In normal rats, synapses labeled by Timm histochemistry or dynorphin immunohistochemistry were rarely observed in the supragranular region of the inner molecular layer when examined by electron microscopy. In epileptic rats, sprouted mossy fiber synaptic terminals were frequently observed. The ultrastructural analysis of the types of sprouted synapses revealed that 1) in the supragranular region, labeled synaptic profiles were more frequently axospinous than axodendritic, and many axospinous synapses were perforated; 2) sprouted mossy fiber synaptic terminals formed exclusively asymmetric, putatively excitatory synapses with dendritic spines and shafts in the supragranular region and with the soma of granule cells in the granule cell layer; 3) in contrast to the large sprouted mossy fiber synapses in resected human epileptic hippocampus, the synapses formed by sprouted mossy fibers in rats were smaller; and 4) in several cases, the postsynaptic targets of sprouted synapses were identified as granule cells, but, in one case, a sprouted synaptic terminal formed a synapse with an inhibitory interneuron. The results demonstrate that axospinous asymmetric synapses are the most common type of synapse formed by sprouted mossy fiber terminals, supporting the viewpoint that most sprouted mossy fibers contribute to recurrent excitation in epilepsy.     

癫痫大鼠海马出芽苔藓纤维突触的超微结构特征

目的:探讨匹罗卡品颞叶癫痫大鼠海马出芽苔藓纤维突触的超微结构特征及其在颞叶癫痫发病机制中的作用。方法:采用Timm组化染色标记出芽苔藓纤维突触末端,在电镜下观察新生突触的类型、比例、定位、以及突触后靶成分。结果:颞叶癫痫大鼠齿状回内分子层可见到银标记的突触末端,出芽苔藓纤维突触主要是轴棘型非对称性突触,其次是轴树型非对称性突触,偶可看到出芽轴突和颗粒细胞体形成突触联系。结论:轴棘型非对称性突触是颞叶癫痫大鼠海马出芽苔藓纤维突触的主要类型,出芽苔藓纤维突触的超微结构特性支持重组突触形成重复的兴奋性环路,而且形成的新的兴奋性环路可能在颞叶癫痫的发生与发展中起重要作用。     

Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: Visualization after retrograde transport of biocytin

In complex partial epilepsy and in animal models of epilepsy, hippocampal mossy fibers appear to develop recurrent collaterals, that invade the dentate molecular layer. Mossy fiber collaterals have been proposed to subserve recurrent excitation by forming granule cell-granule cell synapses. This hypothesis was tested by visualizing dentate granule cells and their mossy fibers after terminal uptake and retrograde transport of biocytin. Labeling studies were performed with transverse slices of the caudal rat hippocampal formation prepared 2.6–l70.0 weeks after pilocarpine-induced or kainic acid-induced status epilepticus. Light microscopy demonstrated the progressive growth of recurrent mossy fibers into the molecular layer; the densest innervation was observed in slices from pilocarpine-treated rats that had survived 10 weeks or longer after status epilepticus. Thin mossy fiber collaterals originated predominantly from deep within the hilar region, crossed the granule cell body layer, and formed an axonal plexus oriented parallel to the cell body layer within the inner one-third of the molecular layer. When sprouting was most robust, some recurrent mossy fibers at the apex of the dentate gyrus reached the outer two-thirds of the molecular layer. The distribution and density of mossy fiber-like Timm staining correlated with the biocytin labeling. When viewed with the electron microscope, the inner one-third of the dentate molecular layer contained numerous mossy fiber boutons. In some instances, biocytin-labeled mossy fiber boutons were engaged in synaptic contact with biocytin-labeled granule cell dendrites. Granule cell dendrites did not develop large complex spines (“thorny excrescences”) at the site of synapse formation, and they did not appear to have been permanently damaged by seizure activity. These results establish the validity of Timm staining as a marker for mossy fiber sprouting and support the view that status epilepticus provokes the formation of a novel recurrent excitatory circuit in the dentate gyrus. Retrograde labeling with biocytin showed that the recurrent mossy fiber projection often occupies a considerably greater fraction of the dendritic region than previous studies had suggested. © 1995 Wiley-Liss, Inc.     

海马苔藓纤维发芽与颞叶癫痫的研究进展

颞叶癫痫是部分性发作癫痫的最主要类型，约有40％的人类癫痫起源于颞叶，这与海马结构独特的神经元环路及纤维联系有关。海马结构中异位突触的形成被认为与颞叶癫痫发作有着密切的联系。而在海马结构的突触重排中，研究最多而且被充分证明的就是苔藓纤维发芽（mossy fiber sprouting，MFS）。现就海马MFS的形态学特性、诱发因素、出芽机理及其与颞叶癫痫发作之间的关系作一综述。     

Dissociation of mossy fiber sprouting and electrically-induced seizure sensitivity: rapid kindling versus adaptation

It has been shown that massed stimulation (MS) of the amygdala or hippocampus does not result in seizure progression but in the 'phenomenon of adaptation', whereas alternate day rapid kindling (ADRK) produces reliable kindling (Lothman, E.W., Williamson, J.M., 1994. Brain Res. 649, 71-84). The goal of the present experiment was to determine if the two different effects are due to differences in mossy fiber sprouting and/or different seizure and postictal spike propagation patterns. Nine rats underwent MS (66-70 stimulations separated by 5-min interstimulus interval), six were exposed to ADRK (12 stimulations/day, every 30 min, with 4 stimulus days, each separated by 1 stimulus-free day), five rats served as control. All rats had electrodes implanted bilaterally in dorsal and ventral hippocampi (VH) and 14 of them had additional electrodes in the piriform cortex. Animals were stimulated in the left VH at afterdischarge threshold. There was no potentiation in seizure response 4-7 weeks after MS. In contrast, ADRK produced not only kindling but also ongoing epileptogenesis resulting 4-7 weeks later in spontaneous seizures and development of a prolonged convulsive state in response to the initially subconvulsive stimulus. Epileptiform activity during MS was mostly restricted to VH, whereas during ADRK it spread widely among studied structures including piriform cortex. Afterdischarges during MS were elicited frequently but seizures did not progress beyond stage 2-3. During ADRK, afterdischarges were evoked less frequently but seizures reached stage 4-7 by the end of the 3rd and 4th stimulus days. The fully kindled state was not reached at this time, but epileptogenic changes continued to progress. Seven weeks after the initial stimulation, both groups demonstrated mossy fiber sprouting of similar intensity in VH. We suggest, (1) frequent but predominantly local hippocampal afterdischarges induce mossy fiber sprouting, but this is not sufficient to produce significant enhancement in seizure susceptibility, and (2) the involvement of extra-hippocampal structures, possibly piriform cortex, and formation of an aberrant hippocampal-para-hippocampal circuit is required to result in a condition of progressive epileptogenesis.     

A lasting change in protein phosphorylation associated with septal kindling

Male Holtzman rats stimulated through a right medial septal electrode displayed prominent hippocampal afterdischarges and the progressive development of kindled seizures. Hippocampal synaptic plasma membranes of kindled rats showed a reduction of³²P incorporation into a protein of approximately 50,000 daltons. This change was not present in controls that received twice as many stimulations as kindled rats with a timing that did not lead to kindling. In kindled rats, reduction of³²P incorporation persisted at least 2 months without further stimulation.     

Hippocampal mossy fiber sprouting and elevated trkB receptor expression following systemic administration of low dose domoic acid during neonatal development

We have previously reported that serial systemic injections of low-dose (subconvulsive) domoic acid (DOM) during early postnatal development produces changes in both behavior and hippocampal cytoarchitecture in aged rats (17 months) that are similar to those seen in existing animal models of temporal lobe epilepsy. Herein we report further hippocampal changes, consisting of mossy fiber sprouting and associated changes in the trkB receptor population in young adult (3 months) rats, and further, report that these changes show regional variation throughout the septo-temporal axis of the hippocampus. Groups of Sprague Dawley rat pups were injected daily from postnatal day 8-14 with either saline (n = 23) or 20 microg/kg DOM (n = 25), tested for key indicators of neonatal neurobehavioral development, and then left undisturbed until approximately 90 days of age, at which time brain tissue was removed, hippocampi were dissected, fixed and processed using either Timm's stain to visualize hippocampal mossy fiber sprouting (MFS) or trkB immunohistochemistry to visualize full length trkB receptors. Multiple sections from dorsal, mid, and ventral hippocampus were analyzed separately and all measures were conducted using image analysis software. The results indicate significant increases in MFS in the inner molecular layer in treated animals with corresponding changes in trkB receptor density. Further we identified significant increases in trkB receptor density in the hilus of the dentate gyrus and area CA3 and report increased mossy fiber terminal density in the stratum lucidum in treated rats. The magnitude of these changes differed between sections from dorsal, mid, and ventral hippocampus. We conclude that low dose neonatal DOM produces cytoarchitectural changes indicative of abnormal development and/or synaptic plasticity that are progressive with age and show regional variation within the hippocampal formation.     

Involvement of Group II mGluRs in mossy fiber LTD

Mossy fiber long‐term depression (LTD) has been shown to be triggered by either pharmacological or synaptic activation of Group II metabotropic glutamate receptors (mGluRs) whereas other studies indicate that synaptic activation of mGluRs is very limited. Therefore, we reexamined the role of Group II mGluRs for the induction of mossy fiber LTD. The complete depression of field potentials (fEPSPs) by 1 μM (2S,2′R,3′R)‐2‐(2′,3′‐Dicarboxycyclopropyl)glycine (DCG‐IV) only partially reversed upon removal of the drug but fEPSPs were completely restored by the Group II antagonist 2S‐2‐amino‐2‐(1S,2S‐2‐carboxycyclopropyl‐1‐yl)‐3‐(xanth‐9‐yl)propanoic acid (LY341495) (3 μM). In contrast, fEPSPs returned back to baseline within 30 min after a brief application of 0.2 μM DCG‐IV suggesting that the incomplete reversal of higher concentrations may be due to a residual receptor occupancy rather than to an induction of LTD. LY341495 itself did not increase fEPSPs and also blocked the inhibition of (2S,1′S,2′S)‐2‐(2‐carboxycyclopropyl)glycine (L‐CCG‐I) (20 μM) and (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (ACPD) (10 μM) and its effect was mimicked by CPPG (50 μM). Furthermore, stimulation at 1 Hz for 15 min induced an LTD of 81% ± 3% and 80% ± 4% in the absence and presence of LY341495, respectively (n = 7, 5). Finally, we found that synaptic activation of Group II mGluRs during 15 min of 1‐Hz stimulation only produces an inhibition of release by 8% ± 1% (30°C, n = 3). Our data suggests that pharmacological activation of Group II mGluRs is fully reversible per se and does not produce a long lasting depression and that activation of Group II mGluRs is neither necessary nor sufficient for the induction of mossy fiber LTD. Synapse 63:1060–1068, 2009. © 2009 Wiley‐Liss, Inc.     

Connections of the hippocampal formation in humans: I. The mossy fiber pathway

The hippocampal formation has been one of the most extensively studied cortical regions in rats, yet little is known about the anatomical connections of the hippocampus in primates, especially humans. With the use of an antibody against the calcium-binding protein, calbindin-D28K, in normal autopsy tissue and the neuronal tracers biocytin or biotinylated dextrans in in vitro slice preparations from tissue removed during surgery for intractable epilepsy, we examined the human hippocampal mossy fiber pathway. The injections of biocytin into the dentate granule cell layer labeled neurons in a Golgi-like manner, revealing the presence of basal dendrites on about 30% of the granule cells. The granule cell axons, the mossy fibers, initially formed a diffuse plexus of fibers in the polymorphic layer before organizing into fiber fascicles in the hilar pyramidal region. These fiber fascicles were much more prominent rostrally than caudally. Within the hilus and proximal portions of the extrahilar CA3 field, the mossy fibers ran through the pyramidal cell layer, and while near the transition to field CA2, the fibers turned superficially and crossed the pyramidal layer to run in the stratum lucidum. All of these features, seen following injections of tracer into hippocampal slices from the brains of epileptics, were confirmed by calbindin-staining of mossy fibers in normal brains. Biocytin-labeled mossy fiber axons revealed two characteristic types of enlargements: small varicosities and larger expansions. The expansions were found throughout the neuropil and were highly irregular, diaminobenzidine-dense profiles that had pleiomorphic modes of attachment to the parent axon. Electron microscopic images of these biocytin labeled expansions revealed that they were large synaptic boutons bearing asymmetric synapses. This study indicates that the human mossy fiber pathway shows some minor deviations from the rodent brain but little difference from monkeys. We argue that these changes mirror a phylogenetic growth of the CA3 pyramidal neurons (subfield CA3c) into the hilus rather than an evolutionary change of the mossy fiber pathway. This growth of subfield CA3c and the increase in mossy fibers running through the pyramidal layer (and a presumed accompanying increase in proximal basal dendritic contacts) may reflect a growing role of the projection from the dentate granule cells to subfield CA3c and from there to field CA1 in the primate hippocampus. J. Comp. Neurol. 385:325–351, 1997. © 1997 Wiley-Liss, Inc.     

Cell adhesion molecule L1 modulates nerve-growth-factor-induced CGRP-IR fiber sprouting

Overexpression of nerve growth factor (NGF) using adenoviruses (Adts) after spinal cord injury induces extensive regeneration and sprouting of calcitonin-gene-related peptide immunoreactive (CGRP-IR) fibers, whereas overexpression of cell adhesion molecules (CAMs) has no effect on the normal distribution of these fibers. Interestingly, co-expression of cell adhesion molecule L1 and NGF significantly decreases (p<0.0001) CGRP-IR fiber sprouting within the spinal cord, when compared to NGF alone. Co-expression of cell adhesion molecules NCAM or N-cadherin had no effect on NGF-induced CGRP-IR fiber sprouting. These data demonstrate that reduced sprouting is specific to L1 co-expression and not other cell adhesion molecules. In vitro studies carried out to address potential mechanisms show that neurite outgrowth over astrocytes overexpressing L1 in the presence of NGF is comparable to controls, indicating that other factors present in vivo might be involved in the L1-mediated reduction in sprouting. One potential factor is semaphorin 3A (sema3A), which mediates growth cone collapse of CGRP-positive axons. Recent studies have shown that L1 is important in sema3A receptor signaling for cortical neurons. In our study, co-expression of sema3A indeed reduces neurite outgrowth from DRG neurons by about 40% on L1-expressing astrocytes. Based on these results, we hypothesize that overexpression of L1 potentiates sema3A signaling resulting in reduced sprouting.     

法舒地尔对戊四氮点燃大鼠海马丝切蛋白及苔藓纤维出芽的影响

目的 探讨法舒地尔对戊四氮(PTZ)点燃大鼠海马组织中丝切蛋白(cofilin,非磷酸化形式)表达与苔藓纤维出芽程度关系的影响.方法 210只SD雄性大鼠分成戊四氮组、法舒地尔干预组和生理盐水对照组,采用PTZ慢性点燃癫癎模型,应用SABC法检测cofilin表达,用Timm染色检测苔鲜纤维出芽情况.结果 PTZ组大鼠点燃率、病死率与法舒地尔组比较差异无统计学意义.PTZ组和法舒地尔组CA3区苔藓纤维出芽评分差异无统计学意义,与对照组相比差异均有统计学意义(P＜0.05).PTZ组和法舒地尔组海马非磷酸化cofilin表达差异无统计学意义.结论 丝切蛋白可能通过苔藓纤维出芽与癫癎的发生相关.     

颞叶癫痫患者海马苔藓纤维发芽的实验研究

目的观察颞叶癫痫病人海马齿状回和CA3区苔藓纤维出芽情况。方法癫痫组样本来自12例颞叶癫痫病例的手术切除标本包含海马齿状回和CA3区的脑组织，对照组脑组织样本来自4例非癫痫病的尸检脑组织。应用Timm组织化学染色方法在光镜和电镜水平进行海马结构苔藓纤维发芽的研究。结果光镜下癫痫组可见苔藓纤维穿越海马齿状回颗粒细胞层到达内分子层．CA3区也可见明显的苔藓纤维发芽。癫痫组CA3区和齿状回内分子层苔藓纤维发芽评分高于对照组．统计学上差异有显著性意义。电子显微镜下观察显示癫痫组患者齿状回内分子层可见到银标记的突触末端，主要和树突形成突触连接，所形成的突触为非对称性突触。结论颞叶癫痫可致海马齿状回和CA3区苔藓纤维发芽增加，这可能是难治性癫痫形成的重要机制。     

Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats

Seizures evoked by kainic acid and a variety of experimental methods induce sprouting of the mossy fiber pathway in the dentate gyrus. In this study, the morphological features and spatial distribution of sprouted mossy fiber axons in the dorsal dentate gyrus of kainate-treated rats were directly shown in granule cells filled in vitro with biocytin and in vivo with the anterograde lectin tracer Phaseolus vulgaris leucoagglutinin (PHAL). Sprouted axon collaterals of biocytin-filled granule cells projected from the hilus of the dentate gyrus into the supragranular layer in both transverse and longitudinal directions in kainate-treated rats but were not observed in normal rats. The sprouted axon collaterals projected into the supragranular region for 600–700 μm along the septotemporal axis. Collaterals from granule cells in the infrapyramidal blade crossed the hilus and sprouted into the supragranular layer of the suprapyramidal blade. Sprouted axon segments in the supragranular layer had more terminal boutons per unit length than the axon segments in the hilus of both normal and kainate-treated rats but did not form giant boutons, which are characteristic of mossy fiber axons in the hilus and CA3. Mossy fiber axons in the hilus of kainate-treated rats had more small terminal boutons, fewer giant boutons, and there was a trend toward greater axon length compared with mossy fibers in the hilus of normal rats. With the additional length of supragranular sprouted collaterals, there was an overall increase in the length of mossy fiber axons in kainate-treated rats. The synaptic and axonal remodeling of the mossy fiber pathway could alter the functional properties of hippocampal circuitry by altering synaptic connectivity in local circuits within the hilus of the dentate gyrus and by increasing the divergence of the mossy fiber terminal field along the septotemporal axis. J. Comp. Neurol. 390:578–594, 1998. © 1998 Wiley-Liss, Inc.     

Glial cell line-derived neurotrophic factor modulates kindling and activation-induced sprouting in hippocampus of adult rats

Kindling, a phenomenon in which repeated electrical stimulation of certain forebrain structures leads to an increase in the evoked epileptogenic response, is widely used to investigate the mechanisms of epilepsy. Kindling also results in sprouting of the dentate gyrus mossy fiber pathway and triggers astrocyte hypertrophy and increased volume of the hilus of the dentate gyrus. Our previous studies showed that infusion of the neurotrophin nerve growth factor accelerated the behavioral progression of amygdala kindling and affected kindling-induced structural changes in the brain, whereas intrahilar infusion of another neurotrophin, brain-derived neurotrophic factor, delayed amygdala kindling-induced seizure development and reduced the growth in afterdischarge duration, but had little effect on kindling-induced structural changes. In this paper, we report the effects of infusion of glial cell line-derived neurotrophic factor, a neurotrophic factor of the TGF-beta superfamily having similar central nervous system neuronal targets as brain-derived neurotrophic factor. We show that continuous intraventricular infusion of glial cell line-derived neurotrophic factor inhibits the behavioral progression of perforant path kindling-induced seizures without affecting afterdischarge duration. In addition, we demonstrate that intraventricular administration of glial cell line-derived neurotrophic factor prevents kindling-induced increases in hilar area and blocks mossy fiber sprouting in the CA3 region of the hippocampus. Glial cell line-derived neurotrophic factor did not have a statistically significant effect on the mossy fiber density in the inner molecular layer. Our results raise the possibility that glial cell line-derived neurotrophic factor plays a role in kindling and activation-induced neural growth via mechanisms distinct from those of the neurotrophins.     

戊四氮点燃模型大鼠Cdk5活性与苔藓纤维出芽相关性

目的研究戊四氮(PTZ)点燃模型大鼠细胞周期素依赖性激酶5(Cdk5)活性改变与苔藓纤维出芽(MFS)动态变化的相关性。方法将120只雄性成年大鼠随机分为PTZ组和对照组,PTZ组连续每天腹腔注射PTZ30mg/kg,对照组同时注射等体积生理盐水。按戊四氮第1次给药后3d、1、2、4和6周各随机分为5个亚组。每个亚组再随机分为2个小组:一组用于液体闪烁计数仪测定各时间点大鼠海马的Cdk5活性;另一组用于Timm染色检测苔藓纤维出芽情况。结果 PTZ组MFS评分3d时增加,2周达高峰并维持至6周;海马Cdk5活性3d时增加,2周达高峰,4周下降,6周恢复对照组水平;较对照组有显著差异。额区Cdk5活性各时间点之间及与对照组之间均无显著性差异。结论 Cdk5可能通过活性增高参与苔藓纤维出芽,从而促使癫发生。     

Long-term potentiation trains induce mossy fiber sprouting

It has been shown that both amygdaloid and hippocampal kindling induce sprouting of the mossy fibers in the dentate gyrus. In this study, we investigated whether non-epileptogenic stimulation could also induce mossy fiber sprouting. Long-term potentiation (LTP) was induced in the dentate gyrus by the application of brief, high-frequency trains to the perforant path. The potentiating stimulation was applied each day for 10 days, and the tissue was prepared for Timm labelling 7 days later. Sprouting was significantly increased in the LTP group compared to the implanted control rats. These results suggest that mossy fiber sprouting is not damage-induced and is dependent on neuronal activation.     

Revisiting the role of the hippocampal mossy fiber synapse

The mossy fiber pathway has long been considered to provide the major source of excitatory input to pyramidal cells of hippocampal area CA3. In this review we describe anatomical and physiological properties of this pathway that challenge this view. We argue that the mossy fiber pathway does not provide the main input to CA3 pyramidal cells, and that the short‐term plasticity and amplitude variance of mossy fiber synapses may be more important features than their long‐term plasticity or absolute input strength. Hippocampus 2001;11:408–417. © 2001 Wiley‐Liss, Inc.