methylazoxymethanol and Epilepsy

Cortical dysplasia of various types, reflecting abnormalities of brain development, have been closely associated with epileptic activities. Yet, there remains considerable discussion about if/how these structural lesions give rise to seizure phenomenology. Animal models have been used to investigate the cause-effect relationships between aberrant cortical structure and epilepsy. In this article, we discuss three such models: (1) the Eker rat model of tuberous sclerosis, in which a gene mutation gives rise to cortical disorganization and cytologically abnormal cellular elements; (2) the p35 knockout mouse, in which the genetic dysfunction gives rise to compromised cortical organization and lamination, but in which the cellular elements appear normal; and (3) the methylazoxymethanol-exposed rat, in which time-specific chemical DNA disruption leads to abnormal patterns of cell formation and migration, resulting in heterotopic neuronal clusters. Integrating data from studies of these animal models with related clinical observations, we propose that the neuropathologic features of these cortical dysplastic lesions are insufficient to determine the seizure-initiating process. Rather, it is their interaction with a more subtly disrupted cortical "surround" that constitutes the circuitry underlying epileptiform activities as well as seizure propensity and ictogenesis.

Topics: Animals; Carcinogens; Disease Models, Animal; Epilepsy; Female; Humans; Malformations of Cortical Development; Methylazoxymethanol Acetate; Mice; Mice, Knockout; Phosphotransferases; Pregnancy; Rats; Tuberous Sclerosis

In the last decade, the recognition of the high frequency of cortical malformations among patients with epilepsy especially children, has led to a renewed interest in the study of the pathophysiology of cortical development. This field has also been spurred by the recent development of several experimental genetic and non-genetic, primarily rodent, models of cortical malformations. Epileptiform activity in these animals can appear as spontaneous seizure activity in vivo, in vitro hyperexcitability, or reduced seizure susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that mimics human microgyria, hyperexcitability is caused by a reorganization of the network in the borders of the malformation. In the prenatal methylazoxymethanol model, that causes a diffuse cortical malformation, hyperexcitability is associated with alteration of firing properties of discrete neuronal subpopulations together with the formation of bridges between normally unconnected structures. In agreement with clinical evidence, these experimental data suggest that cortical malformations can both form epileptogenic foci and alter brain development in a manner that causes a diffuse hyperexcitability of the cortical network.

Topics: Abnormalities, Drug-Induced; Animals; Cerebral Cortex; Disease Models, Animal; Epilepsy; Hippocampus; Humans; Methylazoxymethanol Acetate; Mice; Mice, Knockout; Mitosis; Mutation; Nervous System Malformations; Neural Conduction; Neural Pathways; Rats; Rats, Mutant Strains; Teratogens

Malformation of cortical development (MCD) is one of the main causes of intractable epilepsy in childhood. We explored a treatment based on molecular changes using an infant rat model of methylazoxymethanol (MAM)-induced MCD established by injecting MAM at gestational day 15. The offspring were sacrificed on postnatal day (P) 15 for proteomic analysis, which revealed significant downregulation in the synaptogenesis signaling pathway in the cortex of MCD rats. Recombinant human insulin-growth factor-1 (rhIGF-1) was injected from P12 to P14 twice daily and the effect of IGF1 on N-methyl-D-aspartate (NMDA)-induced spasms (15 mg/kg of NMDA, i.p.) was tested; the onset of P15 single spasm was significantly delayed (p = 0.002) and the number of spasms decreased (p < 0.001) in rhIGF1-pretreated rats (n = 17) compared to those in VEH-treated rats (n = 18). Electroencephalographic monitoring during spasms showed significantly reduced spectral entropy and event-related spectral dynamics of fast oscillation in rhIGF-1 treated rats. Magnetic resonance spectroscopy of the retrosplenial cortex showed decreased glutathione (GSH) (p = 0.039) and significant developmental changes in GSH, phosphocreatine (PCr), and total creatine (tCr) (p = 0.023, 0.042, 0.015, respectively) after rhIGF1 pretreatment. rhIGF1 pretreatment significantly upregulated expression of cortical synaptic proteins such as PSD95, AMPAR1, AMPAR4, NMDAR1, and NMDAR2A (p < 0.05). Thus, early rhIGF-1 treatment could promote synaptic protein expression, which was significantly downregulated by prenatal MAM exposure, and effectively suppress NMDA-induced spasms. Early IGF1 treatment should be further investigated as a therapeutic strategy in infants with MCD-related epilepsy.

Topics: Animals; Disease Models, Animal; Epilepsy; Female; Humans; Infant; Insulin-Like Growth Factor I; N-Methylaspartate; Pregnancy; Proteomics; Rats; Spasm

Periventricular nodular heterotopia (PNH) is, in humans, often associated with difficult-to-control epilepsy. However, there is considerable controversy about the role of the PNH in seizure generation and spread. To study this issue, we have used a rat model in which injection of methylazoxymethanol (MAM) into pregnant rat dams produces offspring with nodular heterotopia-like brain abnormalities.. Electrophysiologic methods were used to examine the activity of the MAM-induced PNH relative to activity in the neighboring hippocampus and overlying neocortex. Recordings were obtained simultaneously from these three structures in slice preparations from MAM-exposed rats and in intact animals. Bath application or systemic injection of bicuculline was used to induce epileptiform activity.. In the in vitro slice, epileptiform discharge was generally initiated in hippocampus. In some cases, independent PNH discharge occurred, but the PNH never "led" discharges in hippocampus or neocortex. Intracellular recordings from PNH neurons confirmed that these cells received synaptic drive from both hippocampus and neocortex, and sent axonal projections to these structures-consistent with anatomic observations of biocytin-injected PNH cells. In intact animal preparations, bicuculline injection resulted in epileptiform discharge in all experiments, with a period of ictal-like electrographic activity typically initiated within 2-3 min after drug injection. In almost all animals, the onset of ictus was seen synchronously across PNH, hippocampal, and neocortical electrodes; in a few cases, the PNH electrode (histologically confirmed) did not participate, but in no case was activity initiated in the PNH electrode. Interictal discharge was also synchronized across all three electrodes; again, the PNH never "led" the other two electrodes, and typically followed (onset several milliseconds after hippocampal/neocortical discharge onset).. These results do not support the hypothesis that the PNH lesion is the primary epileptogenic site, since it does not initiate or lead epileptiform activity that subsequently propagates to other brain regions.

Topics: Action Potentials; Animals; Disease Models, Animal; Epilepsy; Female; Hippocampus; In Vitro Techniques; Lysine; Male; Methylazoxymethanol Acetate; Neocortex; Neurons; Periventricular Nodular Heterotopia; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Teratogens

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.

Topics: Animals; Animals, Newborn; Cell Differentiation; Cell Movement; Cell Proliferation; Cerebral Cortex; Choristoma; Disease Models, Animal; Epilepsy; Female; Hippocampus; Methylazoxymethanol Acetate; Nervous System Malformations; Neuroglia; Neurons; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Stem Cells; Teratogens

Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. Using whole cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation i.e., rats exposed to methylazoxymethanol (MAM) in utero. Analysis revealed that the late N-methyl-D-aspartate (NMDA) receptor-mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burst-like responses. Focal application of glutamate (10 mM) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 microM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor (NMDAR)-mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDAR function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Epilepsy; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Methylazoxymethanol Acetate; N-Methylaspartate; Patch-Clamp Techniques; Piperidines; Rats

Experimentally induced heterotopia exhibit many of the anatomical features characteristic of cortical malformations in children with early-onset epilepsy. We used extracellular field potential recordings from the dorsal hippocampus of intact adult rats to determine whether the excitability of CA1 pyramidal cells was enhanced in rats with experimentally induced hippocampal dysplasia. Electrical stimulation of afferent fibers resulted in more robust population responses in the CA1 region of methylazoxymethanol (MAM)-treated rats vs the controls. The local population of CA1 pyramidal neurons was more excitable in the MAM-treated rat than in the control animals after synaptic activation. These results suggest that the excitability of the CA1 region in rats with hippocampal dysplasia is greater than that in control animals.

Topics: Animals; Bicuculline; Disease Models, Animal; Dose-Response Relationship, Radiation; Electric Stimulation; Epilepsy; Evoked Potentials; Female; GABA Antagonists; Hippocampus; Male; Methylazoxymethanol Acetate; Neurons; Potassium Acetate; Pregnancy; Rats; Rats, Sprague-Dawley

To study voltage-dependent calcium currents (VDCCs) on hippocampal heterotopic neurons by using whole-cell patch-clamp techniques in brain slices prepared from methylaxozymethanol (MAM)-exposed rats.. Whole-cell voltage-clamp recordings were obtained from visually identified neurons in acute brain slices by using an infrared differential interference contrast (IR-DIC) video microscopy system. Heterotopic neurons were compared with normotopic pyramidal cells in hippocampal slices from MAM-exposed rats or CA1 pyramidal neurons in slices from controls.. Heterotopic neurons expressed a prominent VDCC, which exhibited a peak current maximum around -30 mV (holding potential, -60 mV) and an inactivation time constant of 48.2 +/- 2.4 ms (n = 91). VDCC peak current and inactivation time constants were similar for normotopic (n = 92) and CA1 pyramidal cells (n = 40). Pharmacologic analysis of VDCC, on heterotopic, normotopic, and CA1 pyramidal cells, revealed an approximately 70% blockade of peak Ca2+ current with nifedipine and amiloride (L- and T-type channel blockers, respectively). Inhibition of VDCC, for all three cell types, also was similar when more specific Ca2+ channel antagonists were used [e.g., omega-conotoxin GVIA (N-type), omega-agatoxin KT (P/Q-type), and sFTX-3.3 (P-type)]. VDCC modulation by norepinephrine (NE) or adrenergic receptor-specific agonists [clonidine (alpha2), isoproterenol (beta), and phenylephrine (alpha1)] was similar for heterotopic and CA1 pyramidal cells.. Heterotopic neurons do not appear to exhibit Ca2+ channel abnormalities that could contribute to the reported hyperexcitability associated with MAM-exposed rats.

Topics: Animals; Calcium; Calcium Channels; Choristoma; Disease Models, Animal; Electrophysiology; Epilepsy; Female; Hippocampus; Humans; In Vitro Techniques; Methylazoxymethanol Acetate; Nervous System Malformations; Neurons; Patch-Clamp Techniques; Potassium Channels; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Teratogens

Children with brain malformations often exhibit an intractable form of epilepsy. Although alterations in cellular physiology and abnormal histology associated with brain malformations has been studied extensively, synaptic function in malformed brain regions remains poorly understood. We used an animal model, rats exposed to methylazoxymethanol (MAM) in utero, featuring loss of lamination and distinct nodular heterotopia to examine inhibitory synaptic function in the malformed brain. Previous in vitro and in vivo studies demonstrated an enhanced susceptibility to seizure activity and neuronal hyperexcitability in these animals. Here we demonstrate that inhibitory synaptic function is enhanced in rats exposed to MAM in utero. Using in vitro hippocampal slices and whole-cell voltage-clamp recordings from visualized neurons, we observed a dramatic prolongation of GABAergic IPSCs onto heterotopic neurons. Spontaneous IPSC decay time constants were increased by 195% and evoked IPSC decay time constants by 220% compared with age-matched control CA1 pyramidal cells; no change in IPSC amplitude or rise time was observed. GABA transport inhibitors (tiagabine and NO-711) prolonged evoked IPSC decay kinetics of control CA1 pyramidal cells (or normotopic cells) but had no effect on heterotopic neurons. Immunohistochemical staining for GABA transporters (GAT-1 and GAT-3) revealed a low level of expression in heterotopic cell regions, suggesting a reduced ability for GABA reuptake at these synapses. Together, our data demonstrate that GABA-mediated synaptic function at heterotopic synapses is altered and suggests that inhibitory systems are enhanced in the malformed brain.

Topics: Animals; Carrier Proteins; Choristoma; Disease Models, Animal; Epilepsy; Female; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Hippocampus; In Vitro Techniques; Male; Membrane Proteins; Membrane Transport Proteins; Methylazoxymethanol Acetate; Nervous System Malformations; Neural Inhibition; Neurons; Organic Anion Transporters; Patch-Clamp Techniques; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Synapses

Neuronal migration disorders (NMDs) can be associated with neurological dysfunction such as mental retardation, and clusters of disorganized cells (heterotopias) often act as seizure foci in medically intractable partial epilepsies. Methylazoxymethanol (MAM) treatment of pregnant rats results in neuronal heterotopias in offspring, especially in hippocampal area CA1. Although the neurons in dysplastic areas in this model are frequently hyperexcitable, the precise mechanisms controlling excitability remain unclear. Here, we used IR-DIC videomicroscopy and whole cell voltage-clamp techniques to test whether the potent anti-excitatory actions of neuropeptide Y (NPY) affected synaptic excitation of heterotopic neurons. We also compared several synaptic and intrinsic properties of heterotopic, layer 2-3 cortical, and CA1 pyramidal neurons, to further characterize heterotopic cells. NPY powerfully inhibited synaptic excitation onto normal and normotopic CA1 cells but was nearly ineffective on responses evoked in heterotopic cells from stimulation sites within the heterotopia. Glutamatergic synaptic responses on heterotopic cells exhibited a comparatively small, D-2-amino-5-phosphopentanoic acid-sensitive, N-methyl-D-aspartate component. Heterotopic neurons also differed from normal CA1 cells in postsynaptic membrane currents, possessing a prominent inwardly rectifying K(+) current sensitive to Cs(+) and Ba(2+), similar to neocortical layer 2-3 pyramidal cells. CA1 cells instead had a prominent Cs(+)- and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride-sensitive I(h) and negligible inward rectification, unlike heterotopic cells. Thus heterotopic CA1 cells appear to share numerous physiological similarities with neocortical neurons. The lack of NPY's effects on intra-heterotopic inputs, the small contribution of I(h), and abnormal glutamate receptor function, may all contribute to the lowered threshold for epileptiform activity observed in hippocampal heterotopias and could be important factors in epilepsies associated with NMDs.

Topics: Abnormalities, Drug-Induced; Animals; Electrophysiology; Epilepsy; Excitatory Postsynaptic Potentials; Female; Hippocampus; Histocytochemistry; Membrane Potentials; Methylazoxymethanol Acetate; Neocortex; Neuropeptide Y; Potassium Channel Blockers; Potassium Channels; Pregnancy; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Membranes; Teratogens

Human cortical malformations often result in severe forms of epilepsy. Although the morphological properties of cells within these malformations are well characterized, very little is known about the function of these cells. In rats, prenatal methylazoxymethanol (MAM) exposure produces distinct nodules of disorganized pyramidal-like neurons (e.g., nodular heterotopia) and loss of lamination in cortical and hippocampal structures. Hippocampal nodular heterotopias are prone to hyperexcitability and may contribute to the increased seizure susceptibility observed in these animals. Here we demonstrate that heterotopic pyramidal neurons in the hippocampus fail to express a potassium channel subunit corresponding to the fast, transient A-type current. In situ hybridization and immunohistochemical analysis revealed markedly reduced expression of Kv4.2 (A-type) channel subunits in heterotopic cell regions of the hippocampus of MAM-exposed rats. Patch-clamp recordings from visualized heterotopic neurons indicated a lack of fast, transient (I(A))-type potassium current and hyperexcitable firing. A-type currents were observed on normotopic pyramidal neurons in MAM-exposed rats and on interneurons, CA1 pyramidal neurons, and cortical layer V-VI pyramidal neurons in saline-treated control rats. Changes in A-current were not associated with an alteration in the function or expression of delayed, rectifier (Kv2.1) potassium channels on heterotopic cells. We conclude that heterotopic neurons lack functional A-type Kv4.2 potassium channels and that this abnormality could contribute to the increased excitability and decreased seizure thresholds associated with brain malformations in MAM-exposed rats.

Topics: 4-Aminopyridine; Action Potentials; Animals; Cerebral Cortex; Choristoma; Delayed Rectifier Potassium Channels; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Female; Hippocampus; Immunohistochemistry; In Situ Hybridization; In Vitro Techniques; Methylazoxymethanol Acetate; Patch-Clamp Techniques; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Pregnancy; Prenatal Exposure Delayed Effects; Pyramidal Cells; Rats; RNA, Messenger; Shab Potassium Channels; Shal Potassium Channels; Somatosensory Cortex; Tetraethylammonium

Cortical disorganization represents one of the major clinical findings in many children with medically intractable epilepsy. To study the relationship between seizure propensity and abnormal cortical structure, we have begun to characterize an animal model exhibiting aberrant neuronal clusters (heterotopia) and disruption of cortical lamination. In this model, exposing rats in utero to the DNA methylating agent methylazoxymethanol acetate (MAM; embryonic day 15) disrupts the sequence of normal brain development. In MAM-exposed rats, cells in hippocampal heterotopia exhibit neuronal morphology and do not stain with immunohistochemical markers for glia. In hippocampal slices from MAM-exposed animals, extracellular field recordings within heterotopia suggest that these dysplastic cell clusters make synaptic connections locally (i.e. within the CA1 hippocampal subregion) and also make aberrant synaptic contact with neocortical cells. Slice perfusion with bicuculline or 4-aminopyridine leads to epileptiform activity in dysplastic cell clusters that can occur independent of input from CA3. Taken together, our findings suggest that neurons within regions of abnormal hippocampal organization are capable of independent epileptiform activity generation, and can project abnormal discharge to a broad area of neocortex, as well as hippocampus.

Topics: 4-Aminopyridine; Animals; Bicuculline; Brain Diseases; Choristoma; Convulsants; Electrophysiology; Epilepsy; Female; Hippocampus; Methylazoxymethanol Acetate; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Synapses

Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid. On histology, NMD were found in all PG 15 MAM-exposed rats, in comparison to 63% of PG 13, 70% of PG 14, 80% of PG16. Histological features included cortical laminar disorganization, ectopic neurons in the subcortical white matter and in cortical layer I, persistent granular layer, marginal glioneuronal heterotopia, and discrete areas of neuronal ectopia in the CA1 subfield of the hippocampus. Based on the severity of the neuronal migration abnormalities, rats were divided into three categories: severe, moderate, and mild. Severe and moderate NMD were only found in the PG 15 MAM-exposed rats. EEG recording in rats with NMD did not disclose spontaneous seizures; however, rats with severe NMD had higher slow wave activity compared to controls (P < .05). MAM-exposed rats with severe NMD were more susceptible to kainic-induced seizures compared to controls (P < .05). In rats with severe NMD, kainic acid-induced status epilepticus produced hippocampal damage in the CA3/4 region. These results demonstrate that MAM-induced NMD have histological and electrographic characteristics similar to human NMD. The severity of neuronal abnormality depends on the time of transplacental exposure as the most severe NMD were found after exposure to MAM at the time of neuroblastic division. The degree of NMD positively correlates with seizure susceptibility, since only rats with severe NMD have decreased seizure threshold. The occurrence of status epilepticus-induced hippocampal damage in pups with severe NMD suggests that the severely compromised hippocampus is less resistant to seizure-induced injury than the normal developing brain.

Topics: Animals; Behavior, Animal; Body Weight; Brain; Brain Mapping; Cell Movement; Disease Models, Animal; Electroencephalography; Epilepsy; Female; Gestational Age; Hippocampus; Litter Size; Maternal-Fetal Exchange; Methylazoxymethanol Acetate; Neurons; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Seizures

Neuronal migration disorders (NMD) are often found in patients with epilepsy. However, the mechanisms linking these two pathologies are not yet fully understood. In this study, we evaluated whether NMD increased kindling seizure susceptibility and seizure-induced acute neuronal damage in the immature brain.. Experimental NMD were produced by exposing pregnant rats (gestation day 15) to methylazoxymethanol acetate (MAM, 25 mg/kg, ip). Seizures were induced in rat pups (postnatal day 15) transplacentally exposed to MAM and controls by hippocampal kindling. Afterdischarge (AD) threshold and duration, seizure stage, and number of stimulations required to reach each seizure stage were recorded. Acute seizure-induced damage was histologically assessed in Nissl-stained and silver-impregnated hippocampal tissue 24 h after kindling.. Rat pups with NMD had a significantly lower AD threshold than controls (91+/-18 vs. 163+/-23 microA; p < 0.05). Furthermore, rats with NMD required fewer stimulations to reach seizure stage 3.5 and 4 than did controls. Additionally, rats with NMD had longer AD the second day of stimulation (2,094+/-416 s vs. 1,755+/-353 s; p < 0.05). Histologic examination revealed that in rats with NMD, acute seizure-induced neuronal hippocampal damage occurred bilaterally in CA3 hippocampal neurons.. The lowered AD threshold and more rapid kindling to stages 3.5 and 4 indicate that in the presence of severe NMD, hippocampal kindling is facilitated. Furthermore, this study suggests that in the immature brain, seizure-induced hippocampal neuronal damage occurs if there is an underlying pre-existing pathology.

Topics: Animals; Animals, Newborn; Cell Count; Cerebral Cortex; Electric Stimulation; Epilepsy; Female; Hippocampus; Kindling, Neurologic; Methylazoxymethanol Acetate; Mitosis; Neurons; Pregnancy; Rats

Changes in EEG and susceptibility to electrically induced seizures were examined in the ferret with lissencephaly produced by exposure to a single injection of methylazoxymethanol acetate (MAM Ac) given to the pregnant jill on gestation day 32. Ten lissencephalic and 11 normal ferrets were chronically implanted with 14 cortical stainless steel electrodes. EEG records were sampled from various stages of the sleep/awake cycle. Six of each group were subjected to electrical stimulation for seizure threshold. Although the number of stimulations and the current intensity required to produce epileptiform afterdischarges (AD) and seizures were not different between the two groups, the lissencephalic ferrets had significantly longer AD and seizures, and a greater number of generalized seizures, indicating an enhanced seizure susceptibility. The EEG of the lissencephalic ferrets was characterized by increased slow wave activity within the low theta band range, extreme spindle activity, focal or multifocal slow and sharp waves, spikes, or spike and slow wave complexes. The differences in the EEG were more pronounced during drowsiness and sleep stages. The brains of all of the treated animals were lissencephalic and hydrocephalic, and weighed significantly less than those of the normals. The cerebral cortex was thin and flattened, with the parieto-occipital region most severely affected. Heterotopic foci were found in the cerebellum as well as in the cerebral cortex. Abnormalities in the configuration of the cerebellar folia were also seen. Comparison between the electrophysiological and neuropathological data suggests that the extent of the extreme spindle activity, and longer AD and seizure duration depended on the degree of cerebellar dysplasia, whereas the EEG focal abnormalities were related to lesions in the cerebral hemispheres.

Topics: Animals; Cerebral Cortex; Electric Stimulation; Electroencephalography; Epilepsy; Female; Ferrets; Male; Methylazoxymethanol Acetate; Sleep; Syndrome