Do Interictal Discharges Promote or Control Seizures? Experimental Evidence from an In Vitro Model of Epileptiform Discharge

Summary: Interictal and ictal discharges are recorded from limbic structures in temporal lobe epilepsy patients. In clinical practice, interictal spikes are used to localize the epileptogenic area, but they also are assumed to promote ictal events. Here I review data obtained from combined slices of mouse hippocampus–entorhinal cortex that indicate an inverse relation between interictal and ictal events. In this preparation, application of 4-aminopyridine or Mg²⁺-free medium induce (a) interictal discharges that originated from CA3 and propagate (via the Schaffer collaterals) to CA1 and entorhinal cortex, to return to the hippocampus through the dentate area; and (b) ictal discharges that initiate in the entorhinal cortex and propagate to the hippocampus via the dentate gyrus. Interictal activity occurs throughout the experiment (up to 6 h), whereas ictal discharges disappear after 1–2 h. Schaffer collateral cut abolishes interictal discharges in CA1, entorhinal cortex, and dentate and reestablishes entorhinal ictal discharges. Moreover, ictal discharge generation in the entorhinal cortex after Schaffer collateral cut is prevented by mimicking CA3 activity with rhythmic electrical stimulation of CA1 outputs. Thus hippocampal interictal activity controls the ability of the entorhinal cortex to generate seizures. It also may be proposed that Schaffer collateral cut may model the epileptic condition in which CA3 damage results in loss of hippocampal control over the entorhinal cortex. In conclusion, these experiments demonstrate that interictal activity controls rather than promotes ictal events, and functional integrity of CA3 constitutes a critical control mechanism in temporal lobe epilepsy.     

Terminal distribution of projections from the retrosplenial area to the retrohippocampal region in the rat, as studied by anterograde transport of biotinylated dextran amine

The terminal distribution of projections from the retrosplenial area to the retrohippocampal region was examined in the rat with anterograde transport of biotinylated dextran amine. Projections from the retrosplenial granular area (RSG) to the retrohippocampal region terminate predominantly ipsilaterally in layers I, III, V and VI of the presubiculum, layers I and IV–VI of the parasubiculum, the molecular and pyramidal cell layers of the subiculum, and layers I, III, V and VI of the entorhinal area. On the other hand, projections from the retrosplenial agranular area (RSA) terminate predominantly ipsilaterally in layers I and III of the presubiculum and layers V and VI of the entorhinal and perirhinal areas, and ipsilaterally in layers IV–VI of the parasubiculum. The results show that projections from the RSG to the retrohippocampal region are as massive as those from the RSA, and that each retrosplenial area has distinct projection fields in the retrohippocampal region. This suggests that each retrosplenial area may play some distinct functional roles in memory and learning processes such as spatial behavioral learning.     

Inputs from the olfactory bulb and olfactory cortex to the entorhinal cortex in the cat

Summary The spatial organization and laminar distribution of projections from the olfactory bulb and the anterior (PPCa) and posterior (PPCp) divisions of the prepiriform cortex to the entorhinal cortex were studied with anterograde (³H-leucine) and retrograde (WGA-HRP) tracing techniques. After ³H-leucine injections into the olfactory bulb transported labeling was seen over the lateral entorhinal area, except its most medial part, and over the rostral part of the medial entorhinal area. The labeling covers exclusively layer Ia. The lateral and medial entorhinal areas are also reached by fibers from the prepiriform cortex. The projection to the medial entorhinal area has not been described previously. Following injections of ³H-leucine into the PPCa transported labeling is present over the entire expanse of the entorhinal cortex and is located over layer Ib with the greatest density in its superficial part. Injections of ³H-leucine into the PPCp give rise to transported labeling over much of the entorhinal cortex. No labeling was found over the most medial parts of the medial subdivision (VMEA) of the lateral entorhinal area and the medial entorhinal area. Labeling occupies layer Ib, especially its middle part, and layers II and III. Both PPCa and PPCp appear to project most heavily to the dorsal (DLEA) and ventral (VLEA) subdivisions of the lateral entorhinal area. From the retrograde experiments it can be inferred that cells of layers II and III of the PPCa project predominantly to the DLEA, whereas those of the PPCp project predominantly to the VLEA. The MEA receives its heaviest projection from layer II of both PPCa and PPCp. In control experiments with ³H-leucine injections into the endopiriform nucleus it was found that this nucleus projects to the entire expanse of the entorhinal cortex. The fibers distribute to all layers with the exception of layer Ia.Abbreviations AI agranular insular cortex - AL lateral nucleus of the amygdala - BL basolateral nucleus of the amygdala - BM basomedial nucleus of the amygdala - C claustrum - CoA cortical nucleus of the amygdala - DLEA dorsal division of the lateral entorhinal cortex - END endopiriform nucleus - H hippocampus - I granular insular cortex - lot lateral olfactory tractus - MCL mitral cell layer of the olfactory bulb - MEA medial entorhinal area - OB olfactory bulb - PPCa anterior part of the prepiriform nucleus - PPCp posterior part of the prepiriform nucleus - VLEA ventral division of the lateral entorhinal cortex - VMEA ventromedial division of the lateral entorhinal cortex - 35 area 35 of the perirhinal cortex - 36 area 36 of the perirhinal cortex     

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.     

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.     

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease

Summary The allocortical entorhinal region does not gradually transform into the temporal isocortex. Instead, there is an extended stretch of transentorhinal cortex with interdigitation of allocortical and isocortical laminae. The main feature of this transition zone is that the superficial layer of large multipolar nerve cells (Pre-) of the entorhinal region gradually sweeps downward and follows an oblique course through the outer layers. During this course the starshaped nerve cells of Pre- are transformed into pyramidal cells.The layer Pre- projection cells are particularly prone to the development of neurofibrillary changes of the Alzheimer type. In cases of presenile and senile dementia almost all of the layer Pre- projection neurons are changed pathologically. The isocortical pyramidal cells of layers II to IV are far less inclined to develop neurofibrillary changes. In the transentorhinal cortex, the tangle-bearing neurons follow an oblique course through the superficial laminae and are finally located between the isocortical layers III and IV, findings that confirm the assumption that these neurons are constituents of the allocortical layer Pre-.Layer-specific pathology of the profound stratum as well confirms the transentorhinal region as being formed by interdigitating allocortical and isocortical layers.Supported by grants from the Deutsche Forschungsgemeinschaft     

Changes in electrocortical power and coherence in response to the selective cholinergic immunotoxin 192 IgG-saporin

 Changes in brain electrical activity in response to cholinergic agonists, antagonists, or excitotoxic lesions of the basal forebrain may not be reflective entirely of changes in cholinergic tone, in so far as these interventions also involve noncholinergic neurons. We examined electrocortical activity in rats following bilateral intracerebroventricular administration of 192 IgG-saporin (1.8 μg/ventricle), a selective cholinergic immunotoxin directed to the low-affinity nerve growth factor receptor p75. The immunotoxin resulted in extensive loss of choline acetyl transferase (ChAT) activity in neocortex (80%–84%) and hippocampus (93%), with relative sparing of entorhinal-piriform cortex (42%) and amygdala (28%). Electrocortical activity demonstrated modest increases in 1- to 4-Hz power, decreases in 20- to 44-Hz power, and decreases in 4- to 8-Hz intra- and interhemispheric coherence. Rhythmic slow activity (RSA) occurred robustly in toxin-treated animals during voluntary movement and in response to physostigmine, with no significant differences seen in power and peak frequency in comparison with controls. Physostigmine significantly increased intrahemispheric coherence in lesioned and intact animals, with minor increases seen in interhemispheric coherence. Our study suggests that: (1) electrocortical changes in response to selective cholinergic deafferentation are more modest than those previously reported following excitotoxic lesions; (2) changes in cholinergic tone affect primarily brain electrical transmission within, in contrast to between hemispheres; and (3) a substantial cholinergic reserve remains following administration of 192 IgG-saporin, despite dramatic losses of ChAT in cortex and hippocampus. Persistence of a cholinergically modulated RSA suggests that such activity may be mediated through cholinergic neurons which, because they lack the p75 receptor, remain unaffected by the immunotoxin. Received: 22 June 1998 / Accepted: 29 November 1998     

嗅球摘除后大鼠内嗅皮质区神经元变化的实验研究

目的:建立嗅球摘除大鼠模型,观察模型大鼠内嗅皮质区神经元在1 d、3 d、7 d、14 d四个时间点的变化。模型组+茉莉花萃取物,观察大鼠14 d时神经元的变化。与模型组和空白组形成对照,初步探讨茉莉花萃取物通过嗅觉通路对神经元再生作用的可能。方法:嗅球摘除模型建立不同组别,通过尼氏染色观察大鼠内嗅皮质神经元变化,免疫组化观察大鼠内嗅皮质中神经递质的变化。结果:尼氏染色:模型组大鼠内嗅皮质中神经元在受损后1 d、3 d、7 d含量逐步下降;14 d含量明显增加,但仍略低于空白组;吸嗅组(模型组+茉莉花萃取物)内嗅皮质区神经元略高于空白组。免疫组化:模型组大鼠内嗅皮质中5-HT和DA在受损后1 d、3 d、7 d表达逐步减弱,14 d时表达增强,但仍弱于空白组;吸嗅组表达高于14 d,但仍弱于空白组。结论:受损神经被激活后,内嗅皮质有显著的神经再生潜力。初步证明茉莉花萃取物能够通过嗅觉通路加速神经元再生,其机制可能与内嗅皮质中单胺类神经递质的改变相关。     

Impact of temporal coding of presynaptic entorhinal cortex grid cells on the formation of hippocampal place fields

Many behavioural experiments have pointed out the important role played by the hippocampus in spatial navigation. This role was enlightened by the discovery of hippocampal cells in rodents firing only at very specific locations in an environment, the so-called ’place field’. Recently, it has been observed that one synapse upstream of the hippocampus, entorhinal cells fire when the rat is located at any of the vertices of grid fields covering the environment. Furthermore, it was reported that both hippocampal and entorhinal cells have firing activity modulated by the theta local field potential in term of theta phase precession. In a previous report, the authors suggested that the temporal code driven by theta phase precession should play an important role in the building of hippocampal place cells from entorhinal grid cells. Here, with the help of a simpler computational model, we further investigate the implications of our hypothesis. We demonstrate that the nonlinear nature of the shape of the phase precession predicts that place field location are slightly backward shifted according to the direction of the rat.     

Entorhinal cortex of aged subjects with Down’s syndrome shows severe neuronal loss caused by neurofibrillary pathology

In Alzheimer’s disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus – a key structure of the memory system. People with Down’s syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60–74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 ± 914,000 (mean ± standard deviation) to 932,000 ± 504,000. The presence of 2,488,000 ± 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 ± 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of β-amyloid to neuronal loss in the entorhinal cortex is unsubstantial. Received: 8 June 1998 / Revised, accepted: 11 August 1998