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Biomedical subjects

S G Grant

Publications and source records attributed to S G Grant.

At least 19 recordsLinked to original sources
PubMed1999

Induction of human breast cancer cell apoptosis from G2/M preceded by stimulation into the cell cycle by Z-1,1-dichloro-2,3-diphenylcyclopropane.

We have shown previously that Z-1,1-dichloro-2,3-diphenylcyclopropane (a.k.a. Analog II, A(II)) inhibits human breast cancer cell proliferation regardless of estrogen receptor status or estrogen sensitivity, and that its cellular targets include microtubules. In the present study, we investigated the apoptosis-inducing effects of A(II). MCF-7, MCF-7/LY2, and MDA-MB-231 cells all showed nuclear fragmentation in response to 100 microM A(II) when stained with Hoechst 33342 and examined by fluorescence microscopy. Pulsed field gel electrophoretic analysis showed that each of the cell lines also developed specific high molecular weight DNA fragments: a low level of 1-2 Mb fragments appeared after 6 hr, while 30-50 kb fragments accumulated subsequently. At 24 hr of drug exposure, the majority of cells became nonadherent, and the 30-50 kb fragments were restricted to detached MCF-7 and MDA-MB-231 cells. Both adherent and detached MCF-7/LY2 cells exhibited these fragments. A previous study by single-color (propidium) flow cytometry demonstrated that A(II) blocks MDA-MB-231 cells in G2/M of the cell cycle. More refined analyses in the present study showed this same result for MDA-MB-231 cells, but MCF-7 and MCF-7/LY2 cells did not reveal apparent drug-induced cell cycle block. A(II) demonstrated growth inhibitory, cell cycle-perturbing, and hypodiploidy-inducing activity against other human breast carcinoma lines, i.e. BT-20, CAMA-1, and SKBR-3, but no such actions in the non-tumorigenic, "normal" human breast epithelial line MCF-10A. Bromodeoxyuridine labeling and two-color flow cytometric analysis, however, suggested that A(II) caused stimulation into S phase, and that G2/M was the phase of the cell cycle from which cells apoptosed. A(II) caused cell rounding, detachment from the growth matrix, and nuclear shrinkage and fragmentation in parallel with biochemical changes. Cycloheximide inhibited A(II)-induced cell death, indicating that its toxicity requires de novo protein synthesis.

Antineoplastic Agents↗
PubMed1998

Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.

Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.

Animals↗
PubMed1998

Human in vivo somatic mutation measured at two loci: individuals with stably elevated background erythrocyte glycophorin A (gpa) variant frequencies exhibit normal T-lymphocyte hprt mutant frequencies.

A survey of glycophorin A (gpa) in vivo somatic cell mutation in a population of 394 healthy people from 8 to 77 years of age (mean age +/- SD 41 +/- 15 years) revealed a subset of 37 individuals with stably elevated allele-loss and/or allele-loss with duplication variant erythrocyte frequencies (Vf) exceeding 30 x 10(-6). These 37 individuals with gpa outlier Vf are significantly older (P < 0.001) than the remainder of the larger study population from which they were drawn reflecting a highly significant increase in the prevalence of these individuals in the population beyond age 40 years. A study of hpt mutant frequencies (Mf) in the peripheral blood T-lymphocytes of 27 of these individuals, together with 15 matched control individuals with unremarkable gpa Vf, was undertaken to determine if these subjects also displayed elevated mutation frequencies at this independent locus indicative of globally elevated somatic mutation. The hprt Mf in these 27 subjects (geometric mean 11.5 x 10(-6)(dispersion interval 5.8 x 10(-6) to 22.8 x 10(-6)) was not significantly different from that observed in the 15 controls (geometric mean 12.1 x 10(-6)(dispersion interval 5.7 x 10(-6) to 25.5 x 10(-6)). These Mf are higher than typically reported values reflecting the older age distribution of these individuals (arithmetic mean age +/- SD 53 +/- 12 and 50 +/- 16 years for the subjects and controls, respectively). Taken together, these data suggest that several genetic mechanisms may be responsible for producing the gpa outlier Vf observed in these subjects. The observation that hprt Mf were not increased indicates that the majority did not arise by a genome-wide increased rate of somatic mutation detectable at both loci. The fixation and subsequent expansion of 'jackpot' mutations at the gpa locus occurring early in embryonic/fetal development also does not appear to be a predominant mechanism. Some cases may result from a stable over-representation of gpa variant cells, perhaps associated with a marked age-dependent decrease in the number of contributing erythroid stem cells in the bone marrow. The subset that displays elevated allele-loss with duplication Vf involving both gpa alleles may represent individuals with increased rates of somatic recombination. Elevations arising by this mechanism are not detected in the hprt assay, but could be confirmed using a autosomal locus in vivo somatic cell mutation endpoint such as the hla-a assay. Of primary biological significance, these results demonstrate that genetics/stochastic processes leading to the loss of heterozygosity of somatic cells occur ubiquitously in humans and in some individuals this level of somatic mosaicism can approach a frequency of 10(-3) at the gpa locus in erythroid lineage cells.

Adolescent↗
PubMed1998

Induction of forward mutations at the thymidine kinase locus of mouse lymphoma cells: evidence for electrophilic and non-electrophilic mechanisms.

A database of 209 chemicals tested for induction of forward mutations at the heterozygous thymidine kinase (TK +/-) locus in L5178Y mouse lymphoma cells was analyzed for structure-activity relationships using the MultiCASE expert system. Consistent with evidence of several contributing biological mechanisms, these studies suggest that such mutations may occur by more than one mechanism. As might be expected, there was evidence for a component involving direct electrophilic attack on the cellular DNA, in a manner previously established as causative in the induction of mutations in Salmonella. In addition, however, there was also strong evidence for another mechanism or mechanisms involving chromosome missegregation, cellular toxicity or an alternate site of action, such as the microtubules.

Animals↗
PubMed1998

Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo.

NMDA receptors, a class of glutamate-gated cation channels with high Ca2+ conductance, mediate fast transmission and plasticity of central excitatory synapses. We show here that gene-targeted mice expressing NMDA receptors without the large intracellular C-terminal domain of any one of three NR2 subunits phenotypically resemble mice made deficient in that particular subunit. Mice expressing the NR2B subunit in a C-terminally truncated form (NR2B(deltaC/deltaC) mice) die perinatally. NR2A(deltaC/deltaC) mice are viable but exhibit impaired synaptic plasticity and contextual memory. These and NR2C(deltaC/deltaC) mice display deficits in motor coordination. C-terminal truncation of NR2 subunits does not interfere with the formation of gateable receptor channels that can be synaptically activated. Thus, the phenotypes of our mutants appear to reflect defective intracellular signaling.

Amino Acid Sequence↗
PubMed1998

The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells--preliminary comparisons to paclitaxel.

(+)-Discodermolide, a sponge-derived natural product, stabilizes microtubules more potently than paclitaxel despite the lack of any obvious structural similarities between the drugs. It competitively inhibits the binding of paclitaxel to tubulin polymers, hypernucleates microtubule assembly more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant ovarian and colon carcinoma cells. Because paclitaxel shows clinical promise for breast cancer treatment, its effects in a series of human breast cancer cells were compared to those of (+)-discodermolide. Growth inhibition, cell and nuclear morphological, and electrophoretic and flow cytometric analyses were performed on (+)-discodermolide-treated MCF-7 and MDA-MB231 cells. (+)-Discodermolide potently inhibited the growth of both cell types (IC50 < 2.5 nM) at concentrations similar to those observed with paclitaxel. Complete inhibition of growth occurred with 10 nM or greater of each drug and was not reversed by removal. (+)-Discodermolide-treated cells exhibited condensed and highly fragmented nuclei. Flow cytometric comparison of cells treated with either drug at 10 nM, a concentration well below that achieved clinically with paclitaxel, showed both caused cell cycle perturbation and induction of a hypodiploid cell population. (+)-Discodermolide caused these effects more extensively and at earlier time points. The timing and type of high molecular weight DNA fragmentation induced by the two agents was consistent with induction of apoptosis. The results suggest that (+)-discodermolide has promise as a new chemotherapeutic agent against breast and other cancers.

Alkanes↗
PubMed1997

Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels.

We have isolated a novel cDNA, that appears to represent a new class of ion channels, by using the yeast two-hybrid system and the SH3 domain of the neural form of Src (N-src) as a bait. The encoded polypeptide, BCNG-1, is distantly related to cyclic nucleotide-gated channels and the voltage-gated channels, Eag and H-erg. BCNG-1 is expressed exclusively in the brain, as a glycosylated protein of approximately 132 kDa. Immunohistochemical analysis indicates that BCNG-1 is preferentially expressed in specific subsets of neurons in the neocortex, hippocampus, and cerebellum, in particular pyramidal neurons and basket cells. Within individual neurons, the BCNG-1 protein is localized to either the dendrites or the axon terminals depending on the cell type. Southern blot analysis shows that several other BCNG-related sequences are present in the mouse genome, indicating the emergence of an entire subfamily of ion channel coding genes. These findings suggest the existence of a new type of ion channel, which is potentially able to modulate membrane excitability in the brain and could respond to regulation by cyclic nucleotides.

Amino Acid Sequence↗
PubMed1997

A role for the Ras signalling pathway in synaptic transmission and long-term memory.

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.

3T3 Cells↗
PubMed1997

Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene.

To examine the physiological role of the Fyn tyrosine kinase in neurons, we generated transgenic mice that expressed a fyn cDNA under the control of the calcium/calmodulin-dependent protein kinase IIalpha promoter. With this promoter, we detected only low expression of Fyn in the neonatal brain. In contrast, there was strong expression of the fyn-transgene in neurons of the adult forebrain. To determine whether the impairment of long-term potentiation (LTP) observed in adult fyn-deficient mice was caused directly by the lack of Fyn in adult hippocampal neurons or indirectly by an impairment in neuronal development, we generated fyn-rescue mice by introducing the wild-type fyn-transgene into mice carrying a targeted deletion in the endogenous fyn gene. In fyn-rescue mice, Schaffer collateral LTP was restored, even though the morphological abnormalities characteristic of fyn-deficient mice were still present. These results suggest that Fyn contributes, at least in part, to the molecular mechanisms of LTP induction.

Age Factors↗
PubMed1997

Structural and mechanistic bases for the induction of mitotic chromosomal loss and duplication ('malsegregation') in the yeast Saccharomyces cerevisiae: relevance to human carcinogenesis and developmental toxicology.

MultiCASE has the ability to automatically determine the structural features responsible for the biological activity of chemicals. In the present study, 93 chemicals tested for their ability to induce chromosomal 'malsegregation' in the yeast Saccharomyces cerevisiae were analyzed. This 'malsegregation' mimics molecular events that occur during human development and carcinogenesis resulting in an effective loss of one chromosome of an autosomal pair and duplication of the homologue. Structural features associated with the ability to induce such chromosome loss and duplication were identified and compared with those obtained from examination of other toxicological data bases. The most significant structural similarities were identified between the induction of chromosomal malsegregation and several toxicological phenomena such as cellular toxicity, induction of sister chromatid exchanges in vitro and rodent developmental toxicity. Very significant structural similarities were also found with systemic toxicity, induction of micronuclei in vivo and human developmental toxicity. Less significant structural overlaps were found between yeast malsegregation and rodent carcinogenicity, DNA reactivity and mutagenicity, and the induction of chromosome aberrations in vitro and sister chromatid exchanges in vivo. These overlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The predictivity of the SAR model derived from the present data base is relatively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest that it reflects primarily the multiple mechanisms responsible for the induction of chromosomal malsegregation in yeast and the complexity of the phenomenon.

Carcinogens↗
PubMed1997

Radiobiological evaluation of immigrants from the vicinity of Chernobyl.

Eighty individuals (55 adults and 25 children) who were residents of four cities (Kiev, Mozyr, Gomel and Bobrujsk) located 100-200 km from Chernobyl at the time of the accident in 1986 were tested after immigrating to the US from 1989-1991. A whole-body counter was employed to quantitate radiocesium content. In addition, two biological measures of radiation effects, namely, chromosomal integrity using the micronucleus assay and somatic mutation analysis of erythrocytes at the glycophorin A (GPA) locus, were applied to this group. Radiocesium activity in the body ranged from 0 to 56.8 Bq/kg with a mean and standard deviation of 5.0 +/- 8.2 and a median value of 2.0 Bq/kg. Mean radiocesium content by groups was highest in adult males (9.0 +/- 11.7; range 0.21-56.8 Bq/kg) followed by adult females (3.3 +/- 4.5; range 0-21.3 Bq/kg), male children (3.0 +/- 5.7; range 0-20.2 Bq/kg) and lowest in female children (1.6 +/- 3.5; range 0-12.7 Bq/kg). Individuals with the highest radiocesium content in each group belonged to one family that lived in Mozyr (100 km from Chernobyl) until emigrating in 1989. The frequency of lymphocyte micronuclei and erythrocyte GPA allele-loss (O/N) somatic mutations were both significantly correlated with radiocesium content (r=0.57, p=0.002; r=0.75, p=0.002, respectively). The micronucleus frequency also correlated with the estimated internal absorbed dose from radiocesium in a subset of 20 immigrants for whom this calculation was possible (r=0.71, p=0.0005). Altogether, the biomonitoring data indicate that some subjects had radiation doses sufficient to produce gene and chromosomal mutations in blood cells, although these effects cannot be attributed solely to radiocesium exposure.

Adolescent↗
PubMed1997

Glycophorin A as a biological dosimeter for radiation dose to the bone marrow from iodine-131.

The frequency of peripheral blood erythrocyte variants exhibiting allelic loss of glycophorin A (N/M antigen) has been used previously as a biological dosimeter to assess somatic mutations in bone marrow cells from external whole-body irradiation. The aim of the present study was to determine whether this marker could be used as a measure of bone marrow genotoxicity induced by 131I in the treatment of thyroid cancer. Flow cytometry of immunolabeled erythrocytes was performed to enumerate glycophorin A variants before and after eight therapy doses of 131I administered to five patients with differentiated thyroid carcinoma. Bone marrow radiation exposure from each dose was calculated from the integrated retention of 131I in the whole body and in the blood. In addition, the accumulated dose to the bone marrow received from earlier 131I therapy was calculated for each patient. Regression analysis was performed on the frequency of two glycophorin A variant cell types (N/O and N/N) as a function of accumulated dose to the bone marrow. Frequency of N/O variant cells showed a significant dose-related increase with a slope of 10.9 x 10(-6) per sievert. This dose effect is about one-half that previously observed after whole-body external irradiation at high dose rate. This decreased response could be explained by the low dose rate of the radiation to the bone marrow from 131I.

Bone Marrow↗
PubMed1996

Analysis of NMDA receptor mediated synaptic plasticity using gene targeting: roles of Fyn and FAK non-receptor tyrosine kinases.

The NMDA receptor activates a biochemical pathway that regulates long-term changes in synaptic strength. A combination of pharmacological and gene-knockout approaches shows that the postsynaptics signalling cascade initiated by the NMDA receptor involves Fyn tyrosine kinase. We found that Fyn phosphorylates the NMDA receptor and proteins associated with the receptor and proteins associated with the receptor. The interaction of the NMDA receptor with postsynaptic signalling proteins is likely to initiate changes in synaptic strength that contribute to learning and memory.

Animals↗
PubMed1996

Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.

We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf. Cigarette smoking was associated with significantly elevated GPA Vf among active smokers (P = 0.042 for phi/N and P = 0.020 for N/N) and among active and ex-smokers combined (P = 0.014 for N/N). Its influence on phi/N Vf was especially clear among active smokers in the control group (P = 0.005). An effect of smoking, nearly statistically significant, was also observed for the phi/N Vf of control ex-smokers (P = 0.055) and of all active and ex-smokers combined (P = 0.050). Thus, the two characterized chemical exposures experienced by this group of workers and controls appear to produce differential effects on the two independent classes of GPA variants enumerated in the assay. This result suggests that the genotoxicity of these agents is mediated, at least in part, by different genetic mechanisms. Styrene exposure is associated with a specific increase in GPA N/N Vf; these allele loss and duplication variants reflect predominantly somatic recombination mechanisms in erythroid progenitor cells. Tobacco smoke exposure in active and ex-smokers is also associated not only with an increase in N/N Vf but also with an increase in phi/N Vf, reflecting the induction of GPA gene-inactivating mutations, including point mutations and deletions. This finding is consistent with a broad mechanistic spectrum of tobacco smoke genotoxicity associated with this complex mixture of chemical mutagens. Finally, there was no detectable effect of age on phi/N Vf; however, a highly significant (P = 0.0002) increase in N/N Vf with age, even after adjustment for other variables, was observed.

Adult↗
PubMed1995

Focal adhesion kinase in the brain: novel subcellular localization and specific regulation by Fyn tyrosine kinase in mutant mice.

Signaling by tyrosine kinases is required for the induction of synaptic plasticity in the central nervous system. Comparison of fyn, src, yes, and abl nonreceptor tyrosine kinase mutant mice shows a specific requirement for Fyn in the induction of long-term potentiation at CA1 synapses in the hippocampus. To identify components of a Fyn-dependent pathway that may be involved with hippocampus function we examined tyrosine-phosphorylated proteins in kinase mutant mice. We found that nine proteins were hypophosphorylated specifically in fyn mutants. One of the hypophosphorylated proteins was focal adhesion tyrosine kinase (FAK). FAK also showed reduced activity in immunocomplex kinase assays only in fyn mutants. FAK is expressed at very high levels in the brain but in contrast to non-neural cells, FAK was not restricted to focal adhesion contacts. FAK was found in axons, dendrites, and the intermediate filament cytoskeleton of astrocytes. Brain extracts from the mutants also show specific patterns of compensatory changes in the activity of the remaining Src family kinases. Tyrosine phosphorylation is a critical regulator of FAK, and impairments in FAK signal transduction in fyn mutants may contribute to the mutant neural phenotype.

Animals↗
PubMed1995

Sensitivity of somatic mutations in human umbilical cord blood to maternal environments.

To assess the potential effect of maternal environments on human embryonic/fetal somatic mutation, we measured the frequencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT, hprt gene), mutant T lymphocytes (Mf), and glycophorin A (GPA) variant erythrocytes (Vf) of both allele-loss (phi/N) and allele-loss-and-duplication (N/N) phenotypes in umbilical cord blood. The mean hprt Mf (1.40 +/- 1.11 x 10(-6), N = 66) and GPA Vf (phi/N 4.0 +/- 2.2 x 10(-6), N = 114; N/N 2.7 +/- 2.0 x 10(-6), N = 91) were significantly lower than those previously reported for adult populations. In addition, the hprt Mf was significantly higher than that of a published study of newborn cord blood samples from a geographically distant population (0.64 +/- 0.41 x 10(-6), N = 45, P < 0.01; t test, P < 0.01, Mann-Whitney U test). An examination of the demographic data from these two populations led to the sampling of 10 additional newborns specifically matched to the published study for maternal socioeconomic status. The hprt Mf (0.70 +/- 0.49 x 10(-6)) of this selected population was consistent with the published report and significantly lower than that of our initial population (P < 0.03, t test; P < 0.01, Mann-Whitney U test). These results indicate that there is an environmental effect related to maternal socioeconomic status on the frequency of embryonic/fetal somatic mutations. Molecular analyses of hprt mutants from this cohort with elevated Mf revealed a significant decrease in the relative contribution of gross structural mutations to the overall Mf (25 of 38, 66% vs. 34 of 41, 83%, P = 0.024, chi 2 test), suggesting that the higher Mf resulted from an elevated level of "point" mutations. No individual maternal demographic or environmental factor was identified as contributing more significantly than other any factor to the observed variability in hprt Mf or GPA Vf.

Adult↗
PubMed1995

Fyn tyrosine kinase is required for normal amygdala kindling.

To identify specific genes involved with epileptogenesis kindling was examined in mice carrying mutations engineered by gene targeting. Amygdala kindling was tested in mice with a null-mutation in the Fyn tyrosine kinase gene, a mutation that raises the threshold for the induction of long-term potentiation in the hippocampus. The fyn mutants had a normal threshold, duration and stability of epileptiform after-discharge, which is crucial for kindling. Despite the normal after-discharge, fyn mutants showed a striking retardation in the rate of kindling. Once the kindled state was established in fyn mutants it remained stable. This implicates a Fyn-dependent biochemical pathway in the induction but not the maintenance of normal amygdala kindling. fyn is the first gene identified to be required for normal epileptogenesis.

Amygdala↗