Search

The pre-operative assessment and surgical management of patients with dual pathology is challenging. We describe a patient with drug-resistant focal epilepsy with hippocampal sclerosis and extensive periventricular nodular heterotopia in the same hemisphere. The semiology, scalp EEG, and imaging were divergent, but the presence of focal interictal and ictal epileptic discharges of the putative ictal onset zone resulted in successful localization of the epileptogenic zone. A less aggressive resection was performed based on intracranial EEG recording. The patient has been seizure-free for three years since resection. Electroclinical hypotheses and challenges in defining the epileptogenic network are discussed.

Exposure to high levels of glucocorticoids (GCs) during development leads to long-term changes in hypothalamic-pituitary-adrenal (HPA) axis regulation, although little is known about the neural mechanisms that underlie these alterations. In this study, we investigated the effects of late gestational (days 18-22) or postnatal (days 4-6) administration of the GC receptor agonist dexamethasone (DEX) on an apoptosis marker in two brain regions critical to HPA axis regulation, the hippocampus and the hypothalamic paraventricular nucleus (PVN). One day after the final DEX injection, male and female rats were sacrificed, and brains were processed for immunohistochemical detection of cleaved caspase-3, an apoptotic cell death indicator. DEX increased cleaved caspase-3 immunoreactivity in the CA1 hippocampal region of both sexes following prenatal but not postnatal treatment. Prenatal DEX also increased caspase-3 immunoreactivity in the CA3 region, an elevation that tended to be greater in females. In contrast, postnatal DEX resulted in a much smaller, albeit significant, induction in CA3 caspase-3 compared with prenatal treatment. Quantitative real-time PCR analysis revealed that prenatal but not postnatal DEX-induced hippocampal cleaved caspase-3 correlated with elevated mRNA of the proapoptotic gene Bad. Few caspase-3-ir cells were identified within the PVN regardless of treatment age, although postnatal but not prenatal DEX increased this number. However, the region immediately surrounding the PVN (peri-PVN) showed significant increases in caspase-3-ir cells following pre- and postnatal DEX. Together these findings indicate that developmental GC exposure increases apoptosis in HPAaxis-associated brain regions in an age- and sex-dependent manner., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Hippocampal sulcal cavities (HSC) have been speculated to contribute to a higher vulnerability of memory pathways and might be a possible etiological factor in transient global amnesia (TGA). Therefore, we evaluated the influence of HSC on cognitive long-term outcome in TGA-patients., Methods: Fourteen otherwise healthy patients with the clinical syndrome of TGA in their history underwent a high-resolution magnetic resolution imaging and a comprehensive neuropsychological test battery. The neuropsychological control group consisted of 15 healthy subjects and was balanced for age, sex and other risk factors as well as intellectual and social status., Results: Magnetic resolution imaging and neuropsychological testing have been performed 1128 days (median) after the TGA. HSC have been detected in nine of the 14 patients and have been bilateral in eight of them. There were no differences in cognitive performance in patients with and without HSC as well as compared to healthy subjects. Even in patients with greater lesion load, only a slight visuospatial deficit was found., Conclusions: Although an increased incidence of HSCs is detected in TGA patients, cavities are not obligatorily in TGA. Moreover, even patients with hippocampal cavities achieve a full neuropsychological recovery independent of the frequency and size of the hippocampal lesions., (© 2010 The Author(s). European Journal of Neurology © 2010 EFNS.)

Prenatal stress alters neuronal morphology of mesocorticolimbic structures such as frontal cortex and hippocampus in the adult offspring. We investigated here the effects of prenatal stress on the spine density and the dendrite morphology of hippocampal pyramidal neurons and medium spiny cells from nucleus accumbens in prepubertal and adult male offsprings. Sprague-Dawley pregnant dams were stressed by restraining movement daily for 2 hours from gestational day 11 until delivery. Control mothers remained free in their home cage without water and food during the stressful event. Male offsprings from immobilized and control rats were left to grow until postnatal day (PD) 35 for the prepubertal group, and until PD 65 for the adult group. Spontaneous locomotor activity was assessed and then brains were removed to study the dendritic morphology by the Golgi-Cox stain method followed by Sholl analysis. Prenatally stressed animals demonstrated increased locomotion and alterations in spine density in the hippocampus and nucleus accumbens at both ages. However, prepubertal males showed an increase in spine density in the CA1 hippocampus with a decrease in CA3 hippocampus, whereas the adult group showed a decrease in the spine density in both of the regions studied. These results suggest that prenatal stress carried out during the middle of pregnancy affect the spine density and basal dendrites of pyramidal neurons of hippocampus, as well as the dendritic morphology of nucleus accumbens which may reflect important changes in the mesocorticolimbic dopaminergic transmission and behaviors associated with the development of psychiatric diseases such as schizophrenia., (2009 Wiley-Liss, Inc.)

Objective: Our objective in this retrospective study was to assess the hippocampal abnormalities, associate them with various congenital brain malformations, and define the frequency of the association in specific anomaly subgroups., Methods: A total of 62 patients with congenital malformations of the brain who had thin-slice coronal T2-weighted, fluid attenuated inversion recovery, IR, or T1-weighted 3D gradient echo images were retrospectively evaluated for the type of congenital brain malformation and morphological or rotational hippocampal abnormalities. Medical records were reviewed for age, sex, and symptoms., Conclusion: Hippocampal abnormalities are found in 55.8% of all patients with different kinds of congenital brain malformations that are mostly associated with cortical dysplasia, lissencephaly, and total agenesis of the corpus callosum. The severity of the injury may have an effect on the extent of the involvement of the brain.

Hypoxic-ischemic (HI) encephalopathy is an important neurological problem of the perinatal period. Little is known of the long-term progression of HI insults or the maladaptive changes that lead to epilepsy. Using rats with unilateral carotid occlusion followed by hypoxia at postnatal day 7, this study provides an initial analysis of the epilepsy caused by a perinatal HI insult with chronic and continuous behavioral monitoring. The histopathology was investigated at postnatal day 30 and later at > or =6 months of age using cresyl violet, Timm, and rapid Golgi staining and immunocytochemistry. The resultant epilepsy showed an increase in seizure frequency over time, with a preponderance for seizure clusters and behavioral features of an ipsilateral cerebral syndrome. In addition to parasagittal infarcts and porencephalic cysts in severe lesions, columnar neuronal death was found with cytomegaly in isolated groups of dysmorphic cortical neurons. Cortical dysgenesis was seen in the form of deep laminar cell loss, microgyri, white matter hypercellularity, and blurring of the white and gray matter junction. Mossy fiber sprouting was not only detected in the atrophied ipsilateral dorsal hippocampus of HI rats with chronic epilepsy, but was also found in comparable grades in spared ipsi- and contralateral ventral hippocampi. The cortical lesions in this animal model show histological similarities with those found in humans after perinatal HI. The occurrence of cortical abnormalities that are associated with epilepsy in humans correlates with the consequent detection of spontaneous recurrent seizures.

Prenatal exposed to an anti-inflammatory drug is a major problem for the developing central nervous system. It is not well known the effect of prenatal exposed to a non-steroidal anti-inflammatory drug on the hippocampus. Total neuron number in one side of the cornu ammonis (CA) and gyrus dentatus (GD) of the hippocampal formation in control and drug-treated (diclofenac sodium, DS) groups of male rats was estimated using the optical fractionator technique. Each main group has also two subgroups that are 4 weeks old (4W-old) and 20 weeks old (20W-old). In CA, no significant difference between 4W-old DS-treated and their control was found, but a significant difference was observed between 20W-old DS-treated and their controls. A decreasing of neuron number was 12% for 20W-old DS-treated group. In GD, a decreasing of the granule cell number in 4W-old of DS-treated group was seen but an increasing of granule cell number was found in the 20W-old drug-treated rats in comparison to its control group, 7% and 9%, respectively. Although an increasing of neuron number in CA at the control group was seen with age, from 4th week to 20th week (10%), age-dependent substantial granule cell decline (17%) was observed in GD. No age effect on the total cell numbers of CA and GD of the drug-treated groups was seen in comparison to 4W-old week and 20W-old. A pronounced neuron loss observed in the drug-treated group may be attributed to the neurotoxicity of diclofenac sodium (DS) on the developing hippocampal formation. Age-dependent neuron increase in the CA of 20W-old and neuron decline in GD of 20W-old control groups may be a result of a dual effect of saline injection during the fetal life, since these animals were exposed to a stress of 15-day-period of saline injection, prenatal stress. The reason of no age effect on CA and GD cell number in the drug-treated groups may be attributed to the depletion of the progenitor cells due to neurotoxicity of DS in the fetal life of these animals.

While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations., (J. Comp. Neurol. 495:133-148, 2006. (c) 2006 Wiley-Liss, Inc.)

Malnutrition has been associated with a variety of functional and anatomical impairments of the hippocampal formation. One of the more striking of these is widespread loss of hippocampal neurons in postnatally malnourished rats. In the present study we have investigated the effect of prenatal malnutrition on these same neuronal populations, neurons that are all generated during the period of the dietary restriction. In prenatally protein deprived rats, using design-based stereology, we have measured the regional volume and number of neurons in the hilus of the dentate gyrus and the pyramidal cell layers of CA3, CA2, CA1, and the subiculum of 90-day-old animals. These results demonstrated a statistically significant reduction of 20% in neuron numbers in the CA1 subfield, while numbers in the other subfields were unchanged. There was a corresponding significant reduction of 22% in the volume of the CA1 subfield and a significant 14% decrease in the volume of the pyramidal layer of the subiculum. The change in volume of the pyramidal layer of the subiculum without neuron loss may reflect loss of CA1 afferent input to the pyramidal layer. Although the effect of nutritional deprivation on the neuronal population appears to be different in pre- and postnatal malnutrition, both dietary paradigms highlight the vulnerability of key components of the hippocampal trisynaptic circuit (consisting of the dentate granule cell mossy fibers projection to CA3 pyramids and the CA3 projection to the CA1 pyramids), which is an essential circuit for memory and learning., (Copyright (c) 2005 Wiley-Liss, Inc.)

Purpose: Subtle microdysplastic features are found in some patients with hippocampal sclerosis (HS) and refractory temporal lobe epilepsy. The significance of these findings is unknown. We investigated their frequency, relation to the pattern of HS, and clinical associations., Methods: One-hundred forty patients with histologically confirmed HS (mean age at operation, 35 years; 85 women) were analyzed. The presence of HS and subtle structural abnormalities (SSAs) in the mesial temporal lobe and in the lateral neocortical tissue was assessed in detail. Antecedents, seizure characteristics, two verbal memory tests, and outcome in HS patients with and without SSAs were determined., Results: SSAs were found in 60 (43%) of the 140 HS patients, being mesial only in 32 of the 60 cases, and lateral only in nine cases; the remaining 19 cases had both mesial and lateral abnormalities. The frequency of SSA was not related to the pattern of HS or other tested variables. Prolonged febrile convulsions were present in 26 (44%) patients with SSAs, and in 26 (34%) patients (not significant) without SSAs. The outcome after surgery did not differ between patients with SSAs (incidence rate ratio for seizure recurrence, 0.9; 95% confidence interval, 0.5-1.6) compared with patients without SSAs (reference ratio, 1)., Conclusions: Forty-three percent of HS patients have SSAs in their lobectomy specimens. The presence of SSAs does not predict clinical characteristics, such as presence of prolonged febrile convulsions, postsurgical outcome, or neuropsychological performance, nor does it correlate with the histologic pattern of HS.

The septohippocampal pathway contains two separate components: the cholinergic and the GABAergic. Whereas cholinergic fibers terminate on many hippocampal cell types, GABAergic septohippocampal fibers selectively contact the cell bodies of hippocampal interneurons. We examined whether the GABAergic septohippocampal system was altered in reeler mice. First, we found that both components of the septohippocampal pathway in mice present a distribution and target-cell specificity similar to that described in rats. We also show that GABAergic septohippocampal axons terminate on subpopulations of interneurons expressing reelin, which may implicate this extracellular matrix protein in the targeting of septohippocampal axons. We thus examined the septohippocampal pathway in reeler mice defective in Reelin. In contrast to wild-type animals, reeler mice displayed an ectopic location of both cholinergic and GABAergic fibers, which accumulate close to the hippocampal fissure. Despite their altered distribution, GABAergic septal axons maintain their target-cell selectivity innervating exclusively the perisomatic region of hippocampal interneurons. Thus, as in wild type, GABAergic septal fibers formed complex baskets around the cell body of GAD-positive hippocampal neurons in reeler mice. In addition, we found that reeler hippocampi have an altered distribution of hippocampal interneurons expressing PARV or CALB, many of which are located close to the hippocampal fissure. We thus conclude that although reeler mice have an altered distribution of hippocampal interneurons, GABAergic septohippocampal axons nevertheless terminate on their specific target interneurons. Thus, whereas target layer termination of septal fibers is severely impaired in reeler mice, our data indicate that the cell-specific targeting of GABAergic septohippocampal axons is governed by Reelin-independent signals.

Axons travel frequently in bundles to reach their target. After arriving at the target, axon terminals defasciculate, migrate to topographically defined positions, and form synapses with appropriate target neurons. Here we present evidence that the B-type receptors of the erythropoietin-producing hepatocellular (Eph) family and a ligand, ephrin-B3, influence hippocampal axon defasciculation. The EphB receptors are expressed in the hippocampus, and the ligand, ephrin-B3, is transcribed in the lateral septum, the major subcortical target of hippocampal neurons. Ephrin-B3 promotes adhesion of hippocampal neurons to the ligand-expressing substrates in vitro, and the loss of the receptor EphB2 abrogates the effects of ephrin-B3. In mice deficient in EphB2 and EphB3, many hippocampal axons remain in bundles. This phenotype was also observed in mice that were specifically deleted for the cytoplasmic domain of EphB2. These observations indicate that the EphB receptors and their ligand regulate hippocampal axon defasciculation at the septal target, possibly through a receptor-mediated forward signaling mechanism.

The specification and innervation of cerebral subregions is a complex layer-specific process, primed by region-specific transcription factor expression and axonal guidance cues. In Emx2-/- mice, the hippocampus fails to form a normal dentate gyrus as well as the normal layering of principal neurons in the hippocampus proper. Here, we analyzed the late embryonic and postnatal development of the hippocampal formation and its axonal projections in mice lacking Emx2 expression in vitro. As these mutants die perinatally, we used slice cultures of Emx2 mutant hippocampus to circumvent this problem. In late embryonic Emx2-/- cultivated hippocampi, both the perforant path as well as the distribution of calretinin-positive cells are affected. Traced entorhinal afferents in co-cultures with hippocampus from embryonic Emx2-/- mice terminate diffusely in the prospective dentate gyrus in contrast to the layer-specific termination of co-cultures from wild-type littermates. In addition, in brain slice cultures from null mutants the presumptive dentate gyrus failed to develop its normal cytoarchitecture and mature dentate granule cells, including the lack of their mossy fiber projection. Our data indicate that Emx2 is essential for the terminal differentiation of granular cells and the correct formation of extrinsic and intrinsic hippocampal connections.

The hippocampus is critical for forming new long-term memories, but the contributions of the hippocampal commissure (HC) to memory function and hippocampal synaptic plasticity are unclear. To shed light on this issue, we characterized behavioral memory and hippocampal synaptic plasticity in two inbred mouse strains. BALB/cWah1 mice display a range of corpus callosal defects and an intact HC, whereas 9XCA/Wah mice exhibit a complete absence of corpus callosum and a greatly reduced HC. No differences between strains were found in long-term potentiation (LTP) within two synaptic pathways in hippocampal slices. However, paired-pulse facilitation was deficient in area CA1 of slices from 9XCA/Wah, and it was rescued by decreasing extracellular [Ca2+], suggesting that presynaptic calcium dynamics may be altered in this strain. In addition, contextual fear extinction was impaired in 9XCA/Wah mice, but performance on cued fear extinction and on 24 hr memory tests for cued and contextual fear conditioning were not significantly different between strains. Thus, an intact HC is critical for normal extinction of contextual fear. Intact interhemispheric connectivity is not required for acquisition or expression of cued and contextual fear conditioning. LTP was normal in slices from mice that lacked an intact HC, and this was correlated with normal performance on fear conditioning tests. In contrast, impaired short-term synaptic plasticity was correlated with defective contextual memory extinction in mice lacking an intact HC. Thus, the HC in mice is vital for particular aspects of memory function and for short-term synaptic modification in specific hippocampal circuits.

Doublecortin (DCX) is a microtubule-associated protein that is required for normal neocortical and hippocampal development in humans. Mutations in the X-linked human DCX gene cause gross neocortical disorganization (lissencephaly or "smooth brain") in hemizygous males, whereas heterozygous females show a mosaic phenotype with a normal cortex as well as a second band of misplaced (heterotopic) neurons beneath the cortex ("double cortex syndrome"). We created a mouse carrying a targeted mutation in the Dcx gene. Hemizygous male Dcx mice show severe postnatal lethality; the few that survive to adulthood are variably fertile. Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration. In contrast, the hippocampus of both heterozygous females and hemizygous males shows disrupted lamination that is most severe in the CA3 region. Behavioral tests show defects in context and cued conditioned fear tests, suggesting that deficits in hippocampal learning accompany the abnormal cytoarchitecture.

In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.

Neonatal hippocampal lesions in rats produce behavioral and neurochemical abnormalities post-puberty that are used in animal models for developmentally linked pathology in schizophrenia. In one model, adult rats exhibit enhanced sensitivity to the locomotor-activating effects of amphetamine, if they had sustained excitotoxic lesions of the ventral hippocampus on post-natal day 7. The hippocampal elements responsible for these lesion-induced developmental changes have not been fully characterized. The present study assessed the locomotor-activating effects of amphetamine in adult rats that on day 7 had sustained either sham or ibotenic acid lesions of the ventral hippocampus alone ("standard lesions"), or the ventral hippocampus plus surrounding portions of entorhinal cortex and dorsal hippocampus ("large lesions"). "Standard lesions" produced the expected "supersensitive" locomotor response to amphetamine, while "large lesions" did not. No differences between these lesion groups were observed in baseline levels of locomotor activity or habituation. These data suggest that models of enhanced behavioral sensitivity to dopamine agonists after neonatal hippocampal lesions require functionality in the entorhinal cortex and/or dorsal hippocampus. It is possible that the behavioral abnormalities in the "neonatal hippocampal lesion model" reflect, at least in part, aberrant function within spared elements of the hippocampal complex.

Cortical dysplasia is a major cause of intractable epilepsy in children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a key factor in proper neuronal migration in the neocortex. Deletion of p35 leads to severe neocortical lamination defects associated with sporadic lethality and seizures. Here we demonstrate that p35-deficient mice also exhibit dysplasia/ heterotopia of principal neurons in the hippocampal formation, as well as spontaneous behavioral and electrographic seizures. Morphological analyses using immunocytochemistry, electron microscopy, and intracellular labeling reveal a high degree of abnormality in dentate granule cells, including heterotopic localization of granule cells in the molecular layer and hilus, aberrant dendritic orientation, occurrence of basal dendrites, and abnormal axon origination sites. Dentate granule cells of p35-deficient mice also demonstrate aberrant mossy fiber sprouting. Field potential laminar analysis through the dentate molecular layer reflects the dispersion of granule cells and the structural reorganization of this region. Similar patterns of cortical disorganization have been linked to epileptogenesis in animal models of chronic seizures and in human temporal lobe epilepsy. The p35-deficient mouse may therefore offer an experimental system in which we can dissect out the key morphological features that are causally related to epileptogenesis.

Human cortical heterotopia and neuronal migration disorders result in epilepsy; however, the precise mechanisms remain elusive. Here we demonstrate severe neuronal dysplasia and heterotopia throughout the granule cell and pyramidal cell layers of mice containing a heterozygous deletion of Lis1, a mouse model of human 17p13.3-linked lissencephaly. Birth-dating analysis using bromodeoxyuridine revealed that neurons in Lis1+/- murine hippocampus are born at the appropriate time but fail in migration to form a defined cell layer. Heterotopic pyramidal neurons in Lis1+/- mice were stunted and possessed fewer dendritic branches, whereas dentate granule cells were hypertrophic and formed spiny basilar dendrites from which the principal axon emerged. Both somatostatin- and parvalbumin-containing inhibitory neurons were heterotopic and displaced into both stratum radiatum and stratum lacunosum-moleculare. Mechanisms of synaptic transmission were severely disrupted, revealing hyperexcitability at Schaffer collateral-CA1 synapses and depression of mossy fiber-CA3 transmission. In addition, the dynamic range of frequency-dependent facilitation of Lis1+/- mossy fiber transmission was less than that of wild type. Consequently, Lis1+/- hippocampi are prone to interictal electrographic seizure activity in an elevated [K(+)](o) model of epilepsy. In Lis1+/- hippocampus, intense interictal bursting was observed on elevation of extracellular potassium to 6.5 mM, a condition that resulted in only minimal bursting in wild type. These anatomical and physiological hippocampal defects may provide a neuronal basis for seizures associated with lissencephaly.