Chronic Electroconvulsive Seizures Research Articles

Influence of Chronic Electroconvulsive Seizures on Plasticity-Associated Gene Expression and Perineuronal Nets Within the Hippocampi of Young Adult and Middle-Aged Sprague-Dawley Rats.

Electroconvulsive seizure therapy is often used in both treatment-resistant and geriatric depression. However, preclinical studies identifying targets of chronic electroconvulsive seizure (ECS) are predominantly focused on animal models in young adulthood. Given that putative transcriptional, neurogenic, and neuroplastic mechanisms implicated in the behavioral effects of chronic ECS themselves exhibit age-dependent modulation, it remains unknown whether the molecular and cellular targets of chronic ECS vary with age. We subjected young adult (2-3 months) and middle-aged (12-13 months), male Sprague Dawley rats to sham or chronic ECS and assessed for despair-like behavior, hippocampal gene expression, hippocampal neurogenesis, and neuroplastic changes in the extracellular matrix, reelin, and perineuronal net numbers. Chronic ECS reduced despair-like behavior at both ages, accompanied by overlapping and unique changes in activity-dependent and trophic factor gene expression. Although chronic ECS had a similar impact on quiescent neural progenitor numbers at both ages, the eventual increase in hippocampal progenitor proliferation was substantially higher in young adulthood. We noted a decline in reelin⁺ cell numbers following chronic ECS only in young adulthood. In contrast, an age-invariant, robust dissolution of perineuronal net numbers that encapsulate parvalbumin⁺ neurons in the hippocampus were observed following chronic ECS. Our findings indicate that age is a key variable in determining the nature of chronic ECS-evoked molecular and cellular changes in the hippocampus. This raises the intriguing possibility that chronic ECS may recruit distinct, as well as overlapping, mechanisms to drive antidepressant-like behavioral changes in an age-dependent manner.

Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus.

Background:Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape.Methods:We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis. Further, we examined the influence of acute and chronic electroconvulsive seizure on global and residue-specific histone acetylation and methylation levels within the hippocampus, a brain region implicated in the cellular and behavioral effects of electroconvulsive seizure.Results:Acute and chronic electroconvulsive seizure induced a primarily unique, and in certain cases bidirectional, regulation of histone and DNA modifiers, and methyl-CpG-binding proteins, with an overlapping pattern of gene regulation restricted to Sirt4, Mll3, Jmjd3, Gadd45b, Tet2, and Tet3. Global histone acetylation and methylation levels were predominantly unchanged, with the exception of a significant decline in H3K9 acetylation in the hippocampus following chronic electroconvulsive seizure.Conclusions:Electroconvulsive seizure treatment evokes the transcriptional regulation of several histone and DNA modifiers, and methyl-CpG-binding proteins within the hippocampus, with a predominantly distinct pattern of regulation induced by acute and chronic electroconvulsive seizure.

Long-term decrease in immediate early gene expression after electroconvulsive seizures

Electroconvulsive therapy (ECT) is a well-established psychiatric treatment for severe depression. Despite its clinical utility, post-ECT memory deficits are a common side effect. Neuronal plasticity and memory consolidation are intimately related to the expression of immediate early genes (IEG), such as Egr1, Fos and Arc. Changes in IEG activation have been postulated to underlie long-term neuronal adaptations following electroconvulsive seizures (ECS), an animal model of ECT. To test this hypothesis, we used real-time PCR to examine the effect of acute and chronic ECS (8 sessions, one every other day) on the long-term (>24h) expression of IEG Egr1, Fos and Arc in the hippocampus, a brain region implicated both in the pathophysiology of depression as well as in memory function. We observed a transient increase in Egr1 and Fos expression immediately after ECS, followed by a long-term decrease of IEG levels after both acute and chronic ECS. A separate group of animals, submitted to the same chronic ECS protocol and then subjected to open field or passive avoidance tasks, confirmed robust memory deficits 2 weeks after the last chronic ECS. The possible role of IEG downregulation on long-term learning deficits observed following ECS are discussed.

Increase in synaptic hippocampal zinc concentration following chronic but not acute zinc treatment in rats

Electroconvulsive seizures (ECS), one of the most effective treatments of depression, induce mossy fiber sprouting (when assayed by means of synaptic zinc method), and this indicates an increase in the synaptic zinc level in the hippocampus following such therapy. The aim of the present study was to investigate the influence of acute and chronic zinc hydroaspartate administration on the synaptic and total zinc level in the rat hippocampus. We used two methods of zinc determination: (1) zinc-selenium method, which images the pool of synaptic zinc, and (2) flame atomic absorption spectrometry, which assays the total concentration of zinc. Our results indicate that chronic (14 × 65 mg/kg), but not acute, zinc hydroaspartate administration intraperitoneally (i.p.) increases the pool of synaptic zinc in the majority of rat hippocampal layers (by 72–190%), except for the stratum moleculare and stratum radiatum CA, and perforant path DG. On the other hand, no changes were found in total hippocampal zinc level, measured by flame atomic absorption spectrometry. These data suggest that chronic zinc treatment increases the pool of synaptic zinc in the hippocampus, and this effect is similar to that observed following chronic ECS treatment. The measurement of zinc concentration in the whole hippocampus by the flame atomic absorption spectrometry method is not sensitive enough to detect such subtle alteration.

Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum

Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the BDNF and Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. DeltaFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.

Regulation of Activin mRNA and Smad2 Phosphorylation by Antidepressant Treatment in the Rat Brain: Effects in Behavioral Models

Activin is a member of the transforming growth factor-beta family that is involved in cell differentiation, hormone secretion, and regulation of neuron survival. The cellular responses to activin are mediated by phosphorylation of a downstream target, Smad2. The current study examines the influence of chronic electroconvulsive seizures (ECSs), as well as chemical antidepressants, on the expression of activin betaA and the phosphorylation of Smad2 in the rat hippocampus and frontal cortex. Chronic ECSs (10 d) resulted in a significant increase in activin betaA mRNA expression and Smad2 phosphorylation in both the hippocampus and frontal cortex. Chronic fluoxetine did not influence activin betaA expression, but fluoxetine as well as desipramine did increase Smad2 phosphorylation in the frontal cortex. The functional significance of increased activin was further tested by examining the effects of activin infusions into the hippocampus on a behavioral model of depression, the forced swim test (FST). A single bilateral infusion of activin A or activin B into the dentate gyrus of the hippocampus produced an antidepressant-like effect in the FST that was comparable in magnitude with fluoxetine. In contrast, infusion of the activin antagonist inhibin A did not influence behavior but blocked the effect of activin A. The results suggest that regulation of activin and Smad signaling may contribute to the actions of antidepressant treatment and may represent novel targets for antidepressant drug development.

Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways.

Electroconvulsive therapy (ECT) remains the treatment of choice for drug-resistant patients with depressive disorders, yet the mechanism for its efficacy remains unknown. Gene transcription changes were measured in the frontal cortex and hippocampus of rats subjected to sham seizures or to 1 or 10 electroconvulsive seizures (ECS), a model of ECT. Among the 3500-4400 RNA sequences detected in each sample, ECS increased by 1.5- to 11-fold or decreased by at least 34% the expression of 120 unique genes. The hippocampus produced more than three times the number of gene changes seen in the cortex, and many hippocampal gene changes persisted with chronic ECS, unlike in the cortex. Among the 120 genes, 77 have not been reported in previous studies of ECS or seizure responses, and 39 were confirmed among 59 studied by quantitative real time PCR. Another 19 genes, 10 previously unreported, changed by <1.5-fold but with very high significance. Multiple genes were identified within distinct pathways, including the BDNF-MAP kinase-cAMP-cAMP response element-binding protein pathway (15 genes), the arachidonic acid pathway (5 genes), and more than 10 genes in each of the immediate-early gene, neurogenesis, and exercise response gene groups. Neurogenesis, neurite outgrowth, and neuronal plasticity associated with BDNF, glutamate, and cAMP-protein kinase A signaling pathways may mediate the antidepressant effects of ECT in humans. These genes, and others that increase only with chronic ECS such as neuropeptide Y and thyrotropin-releasing hormone, may provide novel ways to select drugs for the treatment of depression and mimic the rapid effectiveness of ECT.

Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures.

G protein-coupled receptor (GPCR) signaling cascades may be key substrates for the antidepressant effects of chronic electroconvulsive seizures (ECS). To better understand changes in these signaling pathways, alterations in levels of mRNA's encoding regulators of G protein signaling (RGS) protein subtypes-2, -4, -7, -8 and -10 were evaluated in rat brain using northern blotting and in situ hybridization. In prefrontal cortex, RGS2 mRNA levels were increased several-fold 2 h following an acute ECS. Increases in RGS8 mRNA were of lesser magnitude (30%), and no changes were evident for the other RGS subtypes. At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS. Levels of RGS2 mRNA were unchanged 24 h following either acute or chronic ECS. In hippocampus, RGS2 mRNA levels were markedly increased 2 h following acute ECS. More modest increases were seen for RGS4 mRNA expression, whereas levels of the other RGS subtypes were unaltered. At 24 h following chronic ECS, RGS7, -8 and -10 mRNA levels were decreased in the granule cell layer, and RGS7 and -8 mRNA levels were decreased in the pyramidal cell layers. Only RGS8 and -10 mRNA levels were significantly reduced in hippocampus 24 h following an acute ECS. Paralleling neocortex, RGS2 mRNA content was unchanged in hippocampus 24 h following either acute or chronic ECS. In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS. The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS. These studies demonstrate subtype-, time-, and region-specific regulation of RGS proteins by ECS, adaptations that may contribute to the antidepressant effects of this treatment.

Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness.

Stress-induced elevation of glucocorticoids is accompanied by structural changes and neuronal damage in certain brain areas. This includes reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus which can be prevented by chronic electroconvulsive seizures and antidepressant drug treatment. In the last years we have bred two strains of rats, one which reacts with congenital helplessness to stress (cLH), and one which congenitally does not acquire helplessness when stressed (cNLH). After being selectively bred for more than 40 generations these strains have lost their behavioural plasticity including their sensitivity to antidepressant treatment. We show here that in cLH rats, acute immobilization stress does not induce a reduction of BDNF expression in the hippocampus which is observed in Sprague--Dawley and cNLH rats. All animals tested exhibited elevated corticosterone levels when stressed, an indication, that in cLH rats regulation of BDNF expression in the hippocampal formation is uncoupled from corticosterone increase induced through stress. This may explain the lack of adaptive responses in this strain.

ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment.

Recent evidence suggests hippocampal and possibly cortical atrophy is associated with major depression. Chronic electroconvulsive seizures (ECS) induce brain-derived neurotrophic factor (BDNF) expression and sprouting of the mossy fiber pathway in the hippocampus, effects that may be related to electroconvulsive therapy's (ECT) mechanism of action. The objective of this study was to investigate the role of NMDA (N-methyl-D-aspartate) receptor in mediating the ECS-induced mossy fiber sprouting and BDNF expression. Timm histochemistry and in situ hybridization methodologies were used to determine the effect of pretreatment with ketamine, an NMDA antagonist, on ECS-induced sprouting and BDNF expression. The results demonstrate the ability of ketamine pretreatment to attenuate ECS-induced sprouting in the dentate gyrus and BDNF expression in the medial prefrontal cortex and the dentate gyrus. In addition, we found a significant decrease in seizure duration with ketamine pretreatment. These data suggest that NMDA receptor activation contributes to both the regulation of neurotrophic factor expression and the morphological changes associated with seizure activity. However, other effects resulting from shortened seizure duration and seizure intensity cannot be excluded. These findings are of increasing interest, as they relate to the use of ECT in the treatment of depression, and the specific anesthetic agents that are used.

Induction of Cyclin-Dependent Kinase 5 in the Hippocampus by Chronic Electroconvulsive Seizures: Role of ΔFosB

The transcription factor DeltaFosB is induced in the hippocampus and other brain regions by repeated electroconvulsive seizures (ECS), an effective antidepressant treatment. The unusually high stability of this protein makes it an attractive candidate to mediate some of the long-lasting changes in the brain caused by ECS treatment. To understand how DeltaFosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express DeltaFosB in this brain region by the use of cDNA expression arrays that contain 588 genes. Of the 430 genes detected, 20 genes were consistently upregulated, and 14 genes were downregulated, by >50%. One of the upregulated genes is cyclin-dependent kinase 5 (cdk5). On the basis of its purported role in regulating neuronal structure, we studied directly whether cdk5 is a true target for DeltaFosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the DeltaFosB-expressing transgenic mice as well as in rats treated chronically with ECS. Chronic ECS treatment also increased, in the hippocampus, the phosphorylation state of tau, a microtubule-associated protein that is a known substrate for cdk5. A 1.6 kb fragment of the cdk5 promoter was cloned, and activity of the promoter was found to be increased after overexpression of DeltaFosB in cell culture. Moreover, mutation of the single consensus activator protein-1 site contained within the cdk5 promoter fragment completely abolished activation of the promoter by DeltaFosB. Together, these results suggest that cdk5 is one target by which DeltaFosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.

Alterations in heavy and light neurofilament proteins in hippocampus following chronic ECS administration

Chronic administration of electroconvulsive seizures (ECS), one of the most effective treatments for depression, induces sprouting of the mossy fibers in the hippocampus. This sprouting requires chronic ECS administration and appears to occur in the absence of hilar neuronal loss. Dynamic regulation of cytoarchitecture plays a vital role in such profound alterations of neuronal morphology. In particular, alterations in the neurofilament protein subunits have been implicated in neurite sprouting, neuronal regeneration, and growth. The present study was carried out to determine the influence of chronic ECS administration on the neurofilament subunits and other molecular markers of neuronal plasticity. Chronic ECS administration decreases the level of phosphorylated heavy neurofilament subunit (NF-H). In addition, the total level of the light neurofilament subunit (NF-L) but not the medium neurofilament subunit (NF-M) is decreased following chronic ECS treatment. Other cytoskeletal proteins, including actin, microtubule-associated protein (MAP-2), and tau, are not influenced by chronic ECS administration. Expression of the growth-associated protein (F1/GAP-43) also remains unchanged following chronic ECS treatment. The changes observed in neurofilaments may be part of the cytoskeletal remodeling that contributes to the mossy fiber sprouting induced by chronic ECS treatment. Synapse 35:137–143, 2000. © 2000 Wiley-Liss, Inc.

Alterations in heavy and light neurofilament proteins in hippocampus following chronic ECS administration.

Chronic administration of electroconvulsive seizures (ECS), one of the most effective treatments for depression, induces sprouting of the mossy fibers in the hippocampus. This sprouting requires chronic ECS administration and appears to occur in the absence of hilar neuronal loss. Dynamic regulation of cytoarchitecture plays a vital role in such profound alterations of neuronal morphology. In particular, alterations in the neurofilament protein subunits have been implicated in neurite sprouting, neuronal regeneration, and growth. The present study was carried out to determine the influence of chronic ECS administration on the neurofilament subunits and other molecular markers of neuronal plasticity. Chronic ECS administration decreases the level of phosphorylated heavy neurofilament subunit (NF-H). In addition, the total level of the light neurofilament subunit (NF-L) but not the medium neurofilament subunit (NF-M) is decreased following chronic ECS treatment. Other cytoskeletal proteins, including actin, microtubule-associated protein (MAP-2), and tau, are not influenced by chronic ECS administration. Expression of the growth-associated protein (F1/GAP-43) also remains unchanged following chronic ECS treatment. The changes observed in neurofilaments may be part of the cytoskeletal remodeling that contributes to the mossy fiber sprouting induced by chronic ECS treatment.

Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures

Stress, which can precipitate and exacerbate depression, causes atrophy and in severe cases death of hippocampal neurons. Atrophy of the hippocampus has also been observed in patients suffering from recurrent major depression. The present study examines the influence of electroconvulsive seizures, one of the most effective treatments for depression, on the morphology and survival of hippocampal neurons. The results demonstrate that chronic administration of electroconvulsive seizures induces sprouting of the granule cell mossy fiber pathway in the hippocampus. This sprouting is dependent on repeated administration of electroconvulsive seizures, reaches a maximum 12 days after the last treatment and is long lasting (i.e. up to six months). Electroconvulsive seizure-induced sprouting occurs in the absence of neuronal loss, indicating that sprouting is not a compensatory response to cell death. This is different from the sprouting induced by kindling or excitotoxin treatment, which induce cell death along with recurrent seizures. Electroconvulsive seizure-induced sprouting is significantly diminished in brain-derived neurotrophic factor heterozygote knockout mice, indicating that this neurotrophic factor contributes to mossy fiber sprouting. However, infusion of brain-derived neurotrophic factor into the hippocampus does not induce sprouting of the mossy fiber pathway. The results demonstrate that chronic administration of electroconvulsive seizures induces mossy fiber sprouting and suggest that increased expression of brain-derived neurotrophic factor is necessary, but not sufficient for the induction on this sprouting. Although the functional consequences remain unclear, sprouting of the mossy fiber pathway would appear to oppose the actions of stress and could thereby contribute to the therapeutic actions of electroconvulsive seizure therapy.

Molecular and Cellular Actions of Chronic Electroconvulsive Seizures

Recent studies have begun to examine the influence of electroconvulsive shock (ECS) on the expression of growth factors in brain, as well as alterations in the function and structure of certain populations of neurons. These studies demonstrate that long-term ECS increases the expression of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, in limbic brain regions. BDNF, a member of the nerve growth-factor family, has been shown to increase the synaptic strength, survival, and growth of adult neurons. Studies in vivo and in cultured cells indicate that the induction of BDNF and TrkB is mediated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), a transcription factor that is activated by cAMP and Ca2+ intracellular pathways. Chronic ECS is also reported to induce sprouting of hippocampal neurons, and studies in BDNF mutant mice indicated that this sprouting is partially dependent on upregulation of BDNF. Increased expression of BDNF and sprouting could also contribute to the altered electrophysiologic properties of hippocampal neurons. These effects of chronic ECS are discussed with respect to recent studies demonstrating that the pathophysiology of stress and depression involves atrophy or death of hippocampal neurons. This work has led to the hypothesis that ECS and antidepressant drugs, via regulation of neurotrophic factors, reverse the atrophy of stress-vulnerable neurons or protect these neurons from further damage.

Essential Role of thefosB Gene in Molecular, Cellular, and Behavioral Actions of Chronic Electroconvulsive Seizures

The role of Fos-like transcription factors in neuronal and behavioral plasticity has remained elusive. Here we demonstrate that a Fos family member protein plays physiological roles in the neuronal, electrophysiological, and behavioral plasticity associated with repeated seizures. Repeated electroconvulsive seizures (ECS) induced isoforms of DeltaFosB in frontal cortex, an effect that was associated with increased levels of the NMDA receptor 1 (NMDAR1) glutamate receptor subunit. Induction of DeltaFosB and the upregulation of NMDAR1 occurred within the same neurons in superficial layers of neocortex. Activator protein-1 (AP-1) complexes composed of DeltaFosB were bound to a consensus AP-1 site in the 5'-promoter region of the NMDAR1 gene. The upregulation of NMDAR1 was absent in mice with a targeted disruption of the fosB gene. In addition, repeated ECS treatment caused progressively shorter motor seizures (tolerance) in both rats and wild-type mice, as well as reduced NMDA-induced inward currents in pyramidal neurons from superficial layers of the neocortex of wild-type mice. These behavioral and electrophysiological effects were also significantly attenuated in fosB mutant mice. These findings identify fosB gene products as transcription factors critical for molecular, electrophysiological, and behavioral adaptations to motor seizures.

Chronic Fos-Related Antigens: Stable Variants of ΔFosB Induced in Brain by Chronic Treatments

Fos family transcription factors are believed to play an important role in the transcriptional responses of the brain to a variety of stimuli. Previous studies have described 35 and 37 kDa Fos-like proteins, termed chronic Fos-related antigens (FRAs), that are induced in brain in a region-specific manner in response to several chronic perturbations, including chronic electroconvulsive seizures, psychotropic drug treatments, and lesions. We show in this study that the chronic FRAs are isoforms of deltaFosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. doffaFosB cDNA encodes the expression of 33, 35, and 37 kDa proteins that arise from a single AUG translation start site. The 35 and 37 kDa proteins correspond to the chronic FRAs that are induced in brain by chronic treatments, whereas the 33 kDa protein corresponds to a Fos-like protein that is induced in brain by acute treatments, findings based on migration on one- and two-dimensional Western blots with anti-FRA and anti-FosB antibodies. Using cells in which deltaFosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa deltaFosB protein exhibits a remarkably long half-life, the 35 kDa DeltaFosB protein exhibits an intermediate half-life, and the 33 kDa deltaFosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa deltaFosB protein is the first to appear after activation of deltaFosB expression. Finally, deltaFosB proteins are shown to possess DNA-binding activity and to exert potent transactivating effects in reporter gene assays. Together, these findings support a scheme wherein deltaFosB, expressed as a 33 kDa protein, is modified to form highly stable isoforms of 35 and 37 kDa. As a result, these stable isoforms gradually accumulate in the brain with repeated treatments to mediate forms of long-lasting neural and behavioral plasticity.

Anterograde transport of endogenous brain-derived neurotrophic factor in hippocampal mossy fibers.

Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are assumed to provide trophic support via a target-derived, retrograde mechanism of action. However, recent studies suggest that neurotrophic factors can act in an autocrine fashion and perhaps even in an anterograde direction similar to neurotransmitters. To further explore this hypothesis, we compared the neuroanatomical pattern of BDNF mRNA and protein in response to electroconvulsive seizures (ECS) or kainic acid-induced seizure activity. Using in situ hybridization, we found that chronic ECS induced BDNF mRNA predominantly in the granule neurons of the dentate gyrus. However, immunohistochemistry with an anti-BDNF antibody revealed that ECS increased endogenous BDNF protein in the mossy fibers, which are composed of axons projecting from the granule neurons of the dentate gyrus to the CA3 pyramidal layer of the hippocampus. Kainic acid administration (10 mg/kg, i.p., once) was used to lesion CA3 neurons selectively, as these are a possible retrograde source of BDNF protein in mossy fibers. Three weeks later, a prolonged elevation of BDNF mRNA in granule neurons, but not elsewhere in hippocampus, was accompanied by an increase in BDNF protein in the mossy fibers. These results suggest that BDNF was transcribed and translated in granule neuron cell bodies but transported in an anterograde direction to provide trophic support of CA3 pyramidal neurons.

Reduced proconvulsant activity of caffeine in rats after a series of electroconvulsive seizures

A variety of neurotransmitter receptor changes occur after a course of electroconvulsive seizures (ECS) in rats, including an increased density of adenosine A1 sites. Adenosine antagonism has been related to the proconvulsant action of methylxanthines such as caffeine. We determined tonic-clonic seizure duration in rats given ECS with caffeine (0-175 mg/kg, IP) after a course of one or six daily ECS. A single day of ECS did not affect the dose-dependent proconvulsant action of caffeine. After six daily ECS, the proconvulsant action of caffeine was reduced. After nine daily ECS, an A1 antagonist (8-cyclopentyl-1,3-dipropylxanthine) and an A2A antagonist (1-allyl-3,7-dimethyl-8-p-sulfophenylxanthine) showed reduced proconvulsant activity. The results suggest that the reduced proconvulsant action of caffeine after chronic ECS depends on adenosine antagonism.

Chronic electroconvulsive seizures increase the expression of serotonin2 receptor mRNA in rat frontal cortex.

The present study examines the influence of electroconvulsive seizure (ECS), as well as antidepressant drugs, on levels of serotonin2 (5-HT2) receptor mRNA in rat frontal cortex. Using a sensitive RNase protective assay, preliminary studies demonstrated the predicted regional distribution for the 5-HT2 receptor mRNA: levels of 5-HT2 mRNA were highest in frontal cortex (2.58 amol/micrograms of total RNA), intermediate in neostriatum, thalamus, and midbrain, and lowest in hippocampus, cerebellum, and choroid plexus. Chronic (10 or 14 days), but not acute (1 or 3 days), ECS treatment significantly increased levels of 5-HT2 receptor mRNA. ECS treatment resulted in a similar time-dependent up-regulation of 5-HT2 receptor ligand binding; chronic, but not acute, ECS treatment significantly increased levels of [3H]ketanserin ligand binding, confirming previous reports. Northern blot analysis demonstrated that 5-HT2 receptor mRNA occurs as two bands (approximately 5 and 6 kb in size), both of which were increased by chronic ECS treatment. The influence of antidepressant drug treatments on 5-HT2 receptor mRNA was also examined. Chronic fluoxetine treatment increased levels of 5-HT2 receptor mRNA, although levels of [3H]ketanserin ligand binding were not altered. In contrast, chronic administration of imipramine, mianserin, and tranylcypromine, treatments that decreased ligand binding, did not decrease levels of 5-HT2 receptor mRNA. In fact, mianserin treatment caused a small, but significant, increase in levels of receptor mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)