Electroconvulsive Seizures Research Articles

Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures

Antidepressant drugs and electroconvulsive seizure (ECS)-treatment, an animal model of electroconvulsive therapy, induce neurogenesis in adult rats. Stress and high levels of corticosterone (CORT) on the contrary inhibit neurogenesis. Hippocampal neurogenesis has been described to occur in an angiogenic niche where proliferation of neural progenitors takes place in an environment with active vascular growth. Here we investigate the effect of ECS-treatment on the proliferation of endothelial cells and neuronal precursors in hippocampus of CORT-treated rats. Bromodeoxyuridine (BrdU) was used to identify dividing cells. The number of newborn neuronal precursors and endothelial cells was quantified in the subgranular zone (SGZ) and the molecular layer (ML) of the dentate gyrus. The increase in neuronal precursor proliferation in the SGZ following ECS-treatment was not inhibited by elevated levels of CORT despite CORT strongly inhibiting ECS-induced endothelial cell proliferation. Also in the ML CORT-treatment inhibited the ECS-induced angiogenic response. We conclude that despite common factors regulating neurogenesis and angiogenesis, ECS-induced proliferation of neuronal precursors can take place even if the angiogenic response is blunted. Whether inhibition of angiogenesis affects other steps in the chain of events leading to the formation of fully integrated granule neurons remains to be elucidated.

Traumatic brain injury during development reduces minimal clonic seizure thresholds at maturity

Post-traumatic seizures affect 12-35% of children after traumatic brain injury (TBI) and are associated with worse cognitive and functional outcome, even after adjustment for severity of injury. Unfortunately, experimental models of pediatric post-traumatic epilepsy are lacking, and pathogenesis remains poorly understood. We have applied a standard model of TBI in immature rats to determine the effect of TBI on electroconvulsive seizure thresholds later in life. Male rats underwent controlled cortical impact to left parietal cortex on post-natal day (PND) 16-18. Hindbrain, forebrain, and limbic seizure thresholds were assessed, respectively, by tonic hindlimb extension (THE), minimal clonic, and partial psychomotor seizure responses during adolescence (PND 34-40) and at maturity (PND 60-63). Post-traumatic seizure thresholds were compared to those obtained in age- and litter-matched sham craniotomy and naïve controls. TBI during immaturity had no clear effect on THE seizure thresholds. In contrast, TBI lowered minimal clonic seizure thresholds at maturity (p<0.05 vs. sham or naïve rats), but not during adolescence. Consequently, minimal clonic seizure thresholds increased with age for sham and naïve rats but remained similar for TBI rats during adolescence and at maturity. TBI also tended to lower partial psychomotor seizure thresholds, which were determined only during adolescence (p<0.1 vs. naïve). Controlled cortical impact causes both focal cortical injury at the site of impact and ipsilateral hippocampal neuronal death. Since minimal clonic seizures are mediated by the forebrain, partial psychomotor seizures by the limbic system, and THE seizures by the brainstem, the observed pattern of changes in post-traumatic seizure thresholds is not surprising. The apparent age-dependent effects of TBI, however, are unexpected and likely due to a combination of attenuated maturational increases and progressive epileptogenesis. Additional study is needed to delineate the relative contributions of these processes. Given the sustained reduction in post-traumatic minimal clonic seizure thresholds, controlled cortical impact may hold promise as an experimental model of pediatric post-traumatic epilepsy.

Astroglia: Not Just Glue

Astroglia: Not Just Glue

Electroconvulsive seizure restores neurogenesis and hippocampus‐dependent fear memory after disruption by irradiation

Ongoing neurogenesis in the adult hippocampus is thought to play a role in learning and memory processes, and in response to antidepressant treatments. Low doses of irradiation (IRR) produce a significant long-lasting inhibitory effect on hippocampal neurogenesis that correlates with long-lasting behavioral deficits. Here we report that electroconvulsive seizure (ECS), which robustly increases adult neurogenesis in naïve animals, also reverses the disruption of neurogenesis produced by IRR exposure. Moreover, we find that vascular endothelial growth factor (VEGF) is an essential mediator of this effect. Expression of VEGF in the granule cell layer (GCL) of the hippocampus is decreased by IRR, and ECS administration reverses this deficit in VEGF. There is a corresponding alteration in the number of endothelial cells, which express VEGF, in the hippocampal GCL following IRR and ECS. We also find that blockade of VEGF signaling attenuates ECS-induced proliferation, and VEGF infusion partially restores proliferation in irradiated animals. To examine the functional consequences of IRR and ECS on neurogenesis, hippocampus-dependent contextual fear conditioning was assessed. We found that following disruption by IRR, ECS restores contextual learning to baseline levels at time points consistent with its effects on neurogenesis. These findings demonstrate that ECS, in part via induction of VEGF, can reverse long-term neurogenesis deficits resulting from IRR, and that these effects have functional consequences on hippocampus-dependent fear memory.

Repeated electroconvulsive seizure induces c-Myc down-regulation and Bad inactivation in the rat frontal cortex

Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-X(L), Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X(L) after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.

Effects of Repeated Electroconvulsive Seizures on Spontaneous Alternation Behavior and Locomotor Activity in Rats

Epileptic patients are at a significantly higher risk for impairments of cognitive function and behavioral abnormalities. In this study, we investigated the effect of repeated electroconvulsive shock (ECS)-induced seizures on the spontaneous alternation behavior in a Y-maze test and the locomotor activity in an open-field test, and examined the effects of anti-epileptic drugs in rats. ECS was administered for seven consecutive days and the Y-maze and open-field tests were performed 24 h after the last ECS administration. The repeated electroconvulsive seizures significantly impaired the spontaneous alternation and increased the locomotor activity. Moreover, these behavioral changes induced by the seven administrations of ECS persisted for at least 28 d. The inhibition of the ECS-induced seizures through the daily pretreatment of the phenytoin (120 mg/kg, intraperitoneally (i.p.)), phenobarbital (60 mg/kg, i.p.) and valproate (400 mg/kg, i.p.) abolished the locomotor hyperactivity in the open-field test. The impaired spontaneous alternation behavior in the Y-maze test was also significantly suppressed by the treatment with phenytoin and valproate. However, phenobarbital injection produced no significant ameliorating effect in the Y-maze test. These results suggest that the inhibition of ECS-induced seizures through phenytoin and valproate injections suppress the development of impairment of spontaneous alternation and the locomotor hyperactivity.

Strain and age affect electroconvulsive seizure testing in rats

Electroconvulsive seizure thresholds were compared between adolescent and mature Sprague--Dawley, Wistar, and Fischer rats. All strains had similar hindbrain or forebrain seizure thresholds as adolescents. As adults, hindbrain or forebrain seizure thresholds were highest for Sprague--Dawley and lowest for Fischer rats. Conversely, limbic seizure thresholds during adolescence were highest for Fischer rats. Additional study is needed to better delineate strain and maturational effects on electroconvulsive seizure testing.

Electroconvulsive Therapy and Antibiotics

Infections are common comorbid conditions in hospitalized patients, including those receiving electroconvulsive therapy (ECT). In this report, we demonstrate the fluoroquinolone class of antibiotics can be associated with prolonged electroconvulsive seizure duration. We describe an 82-year-old woman treated with the fluoroquinolone, moxifloxacin, during a course of ECT. After previously tolerating ECT well, introduction of moxifloxacin for a respiratory tract infection was associated with prolonged seizure duration despite complete resolution of her respiratory complaint. Taken together with other evidence that fluoroquinolones lower seizure threshold, this report suggests fluoroquinolones should be avoided in patients receiving ECT.

Arcadlin Signals Internalization

The abundance of the cell adhesion molecule N-cadherin is one factor that contributes to dendritic spine plasticity. When N-cadherin activity is compromised, spine number is decreased. Yasuda et al . found that conditions that stimulate excitatory synapses, such as maximal electroconvulsive seizure in mice or application of glutamate or agents that elevate the concentration of adenosine 3′,5′-monophosphate (cAMP) to cultured hippocampal neurons, increased the abundance of arcadlin, a protocadherin protein that was recruited to excitatory dendrites. Furthermore, arcadlin coimmunoprecipitated with N-cadherin from rat hippocampi after stimulation, as well as from transfected cultured cells. Cultured cells transfected with arcadlin and N-cadherin exhibited diminished homophilic adhesiveness. Stimulated hippocampal cultures exhibited decreased abundance of N-cadherin at the cell surface (based on a surface biotinylation assay and immunofluorescent analysis). In neurons cultured from acad –/– mice, increases in cAMP concentration did not decrease N-cadherin surface abundance. A yeast two-hybrid screen identified a kinase that the authors named TAO2β, which appears to be an alternative splice variant of TAO2, as a protein that interacted with arcadlin. This interaction was confirmed by coimmunoprecipitation of the two proteins from hippocampi of mice after maximal electroconvulsive seizure and in colocalization studies in transfected cells. TAO2 is a mitogen-activated protein kinase kinase kinase (MAPKKK), and when transfected cells or primary cultures of rat hippocampal neurons were treated with the arcadlin extracellular domain (Acad-EC) to ligate the arcadlin proteins, phosphorylated mitogen-activated protein kinase kinase 3 (MEK3) and p38 MAPK were detected, suggesting that TAO2β is also a p38 MAPKKK. The abundance of arcadlin at the cell surface, as well as that of N-cadherin, was decreased in response to Acad-EC through a mechanism that required TAO2β and p38 activity. TAO2 could not substitute for TAO2β in triggering arcadlin endocytosis, yet endocytosis required p38, suggesting a possible feedback mechanism depending on TAO2β. Indeed, in vitro phosphorylation assays confirmed that TAO2β was a substrate for p38, and, in cells transfected with mutants that lacked the phosphorylation site, the importance of this phosphorylation for triggering endocytosis of arcadlin was confirmed. Finally, the increase in spine density seen in cultured neurons from acad –/– mice was reversed by knockdown of N-cadherin. Thus, arcadlin appears to link the endocytosis of N-cadherin to excitatory stimuli through a MAPK pathway. S. Yasuda, H. Tanaka, H. Sugiura, K. Okamura, T. Sakaguchi, U. Tran, T. Takemiya, A. Mizoguchi, Y. Yagita, T. Sakurai, E. M. De Robertis, Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2β and p38 MAP kinases. Neuron 56 , 456-471 (2007). [PubMed]

Vascular endothelial growth factor is up-regulated after status epilepticus and protects against seizure-induced neuronal loss in hippocampus

Vascular endothelial growth factor (VEGF) is a protein factor which has been found to play a significant role in both normal and pathological states. Its role as an angiogenic factor is well-established. More recently, VEGF has been shown to protect neurons from cell death both in vivo and in vitro. While VEGF’s potential as a protective factor has been demonstrated in hypoxia–ischemia, in vitro excitotoxicity, and motor neuron degeneration, its role in seizure-induced cell loss has received little attention. A potential role in seizures is suggested by Newton et al.’s [Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: Induction of neurotrophic and angiogenic factors. J Neurosci 23:10841–10851] finding that VEGF mRNA increases in areas of the brain that are susceptible to cell loss after electroconvulsive-shock induced seizures. Because a linear relationship does not always exist between expression of mRNA and protein, we investigated whether VEGF protein expression increased after pilocarpine-induced status epilepticus. In addition, we administered exogenous VEGF in one experiment and blocked endogenous VEGF in another to determine whether VEGF exerts a neuroprotective effect against status epilepticus-induced cell loss in one vulnerable brain region, the rat hippocampus. Our data revealed that VEGF is dramatically up-regulated in neurons and glia in hippocampus, thalamus, amygdala, and neocortex 24 h after status epilepticus. VEGF induced significant preservation of hippocampal neurons, suggesting that VEGF may play a neuroprotective role following status epilepticus.

CREB Binding and Activity in Brain: Regional Specificity and Induction by Electroconvulsive Seizure

The transcription factor cyclic adenosine monophosphate response element binding protein (CREB) orchestrates diverse neurobiological processes including cell differentiation, survival, and plasticity. Alterations in CREB-mediated transcription have been implicated in numerous central nervous system (CNS) disorders including depression, anxiety, addiction, and cognitive decline. However, it remains unclear how CREB contributes to normal and aberrant CNS function, as the identity of CREB-regulated genes in brain and the regional and temporal dynamics of CREB function remain largely undetermined. We combined microarray and chromatin immunoprecipitation technology to analyze CREB-DNA interactions in brain. We compared the occupancy and activity of CREB at gene promoters in rat frontal cortex, hippocampus, and striatum before and after a rodent model of electroconvulsive therapy. Our analysis identified >860 CREB binding sites in rat brain. We identified multiple genomic loci enriched with CREB binding sites and find that CREB-occupied transcripts interact extensively to promote cell proliferation, plasticity, and resiliency. We discovered regional differences in CREB occupancy and activity that explain, in part, the diverse biological and behavioral outputs of CREB activity in frontal cortex, hippocampus, and striatum. Electroconvulsive seizure rapidly increased CREB occupancy and/or phosphorylation at select promoters, demonstrating that both events contribute to the temporal regulation of the CREB transcriptome. Our data provide a mechanistic basis for CREB's ability to integrate regional and temporal cues to orchestrate state-specific patterns of transcription in the brain, indicate that CREB is an important mediator of the biological responses to electroconvulsive seizure, and provide global mechanistic insights into CREB's role in psychiatric and cognitive function.

Protein synthesis inhibitors, gene superinduction and memory: Too little or too much protein?

To date, the effects of protein synthesis inhibitors (PSI) in learning and memory processes have been attributed to translational arrest and consequent inhibition of de novo protein synthesis. Here we argue that amnesia produced by PSI can be the direct result of their abnormal induction of mRNA—a process termed gene superinduction. This action exerted by PSI involves an abundant and prolonged accumulation of mRNA transcripts of genes that are normally transiently induced. We summarize experimental evidence for the multiple mechanisms and signaling pathways mediating gene superinduction and consider its relevance for PSI-induced amnesia. This mechanistic alternative to protein synthesis inhibition is compared to models of electroconvulsive seizures and fragile × syndrome associated with enhanced mRNA/protein levels and cognitive deficits.

Stress and electroconvulsive seizure differentially alter GPR56 expression in the adult rat brain

GPR56, a member of the G-protein-coupled receptor family, plays a role in the formation of the frontal and parietal brain lobes and cortical lamination in the embryonic stage. A recent report indicated the existence of GPR56 transcripts in the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) of the adult mouse brain. Both these regions are known to continually produce neural progenitor cells in the adult brain. Here, we demonstrate abundant GPR56 protein expression in the ependymal cell layer and SVZ as well as its reciprocal translational regulation by a 12-day behavioral stress paradigm and 10-day electroconvulsive seizure (ECS) treatment. Our study revealed that GPR56 transcript expression in the hippocampus was regulated by stress and seizure in a manner identical to that in the SVZ. GPR56 expression was downregulated by stress and upregulated by the ECS treatment in both regions, whereas nestin expression showed no changes. Western blot analysis revealed a robust ECS-induced increase in brain-derived neurotrophic factor expression in the wall of the lateral ventricle including the ependymal cell layer and the SVZ, which may provide a possible regulatory mechanism for GPR56 expression. We consider that GPR56 is expressed in the ependymal cell layer and in immature progenitor cells and that its expression is regulated by functional stimulation.

ECT : de la neuroplasticité aux mécanismes d’action

Electroconvulsive therapy (ECT) is one of the most effective treatments for depression. Although it has been used for over 60 years, the basis for its therapeutic effect is still unknown. Structural plasticity within the nervous system such as neurogenesis or mossy fiber sprouting could be involved in the mechanisms underlying the antidepressant effect of several pharmacological antidepressants. But what is the mechanism underlying ECT? Several methodological issues using magnetic resonance spectroscopy for humans and rats found changes in neuronal metabolism during ECT. The levels of N-Acetyl-Aspartate, an amino acid exclusively located in neurons, are increased after ECT; choline, which is believed to represent membrane turn-over, increases as well. These results are in good agreement with ECT induced structural plasticity. Electroconvulsive seizures (ECS), an animal model of ECT, can enhance neurogenesis, particularly in the hippocampal dentate gyrus. A series of seizures increases neurogenesis more than a single shock. In the glucocorticoid paradigm of depression, ECS can increase hippocampal neurogenesis. This suggests that induction of neurogenesis might be implicated in the antidepressant mechanism of ECT. As suggested by previous studies, Brain Derived Neurotrophic Factor (BDNF) is supposed to play a critical role in the action of antidepressants through neuronal plasticity. ECS increases the expression of BDNF. The BDNF gene has four differentially regulated promoters that generate four transcript forms. Studying the regulation of these transcript forms by diverse classes of antidepressant therapeutics, including ECS, suggests that diverse signalling mechanisms may be recruited to regulate BDNF transcripts. Moreover, for ECS, these signalling mechanisms seem to differ from those recruited by excitotoxic cell death phenomena, such as neuronal damage or epileptic seizure models. These results indicate the participation of neuronal plasticity to help account for the antidepressant effect of ECT. However, this relationship is currently not clearly defined, particularly in terms of causality, and will require future studies to unravel it.

A Silver Bullet for the Treatment of Depression?

The search for a rapid-acting antidepressant has been a subject of intense research interest for several decades. The article by Lucas and colleagues in this issue of Neuron provides compelling evidence from preclinical animal models that drugs acting at the serotonin 5-HT(4) receptor could finally achieve this goal. However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans.

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

Apoptosis has been proposed as a contributing cellular mechanism to the structural alterations that have been observed in stress-related mood disorders. Antidepressants, on the other hand, are hypothesized to exert trophic and/or neuroprotective actions. The present study examined the regulation of the major antiapoptotic (Bcl-2, Bcl-xl) and proapoptotic (Bax) genes by repeated unpredictable stress (an animal model of depression) and antidepressant treatments (ADT). In adult rats, exposure to unpredictable stress reduced Bcl-2 mRNA levels in the central nucleus of the amygdala (CeA), cingulate (Cg), and frontal (Fr) cortices. Bcl-xl mRNA was significantly decreased in hippocampal subfields. In contrast, chronic administration of clinically effective antidepressants from four different classes, ie fluoxetine, reboxetine, tranylcypromine, and electroconvulsive seizures (ECS) upregulated Bcl-2 mRNA expression in the Cg, Fr, and CeA. Reboxetine, tranylcypromine, and ECS selectively increased Bcl-xl, but not Bcl-2 mRNA expression in the hippocampus. Chemical ADT but not ECS, robustly enhanced Bcl-2 expression in the medial amygdaloid nucleus and ventromedial hypothalamus. Fluoxetine did not influence Bcl-xl expression in the hippocampus, but it was the only ADT that decreased Bax expression in this region. In the CeA, again in direct contrast to the stress effects, exposure to all classes of ADTs significantly increased Bcl-2 mRNA. The selective regulation of Bcl-xl and Bax in hippocampal subfields and of Bcl-2 in the Cg cortex, amygdala, and hypothalamus suggests that these cellular adaptations contribute to the long-term neural plastic adaptations to stress and ADTs in cortical, hypothalamic, and limbic brain structures.

Dimerization and DNA-Binding Properties of the Transcription Factor ΔFosB

The transcription factor, DeltaFosB, a splice isoform of fosB, accumulates in rodents in a brain-region-specific manner in response to chronic administration of drugs of abuse, stress, certain antipsychotic or antidepressant medications, electroconvulsive seizures, and certain lesions. Increasing evidence supports a functional role of such DeltaFosB induction in animal models of several psychiatric and neurologic disorders. Fos family proteins, including DeltaFosB, are known to heterodimerize with Jun family proteins to create active AP-1 transcription-factor complexes, which bind to DNA specifically at AP-1 consensus sites. We show here, using a range of biochemical and biophysical means, that recombinant, purified DeltaFosB forms homodimers as well, at concentrations less than 500 nM, and that these homodimers specifically bind to DNA oligonucleotides containing AP-1 consensus sequences in the absence of any Jun partner. Our results suggest that, as DeltaFosB accumulates to abnormally elevated protein levels in highly specific regions of the brain in response to chronic stimulation, functional homodimers of DeltaFosB are formed with the potential to uniquely regulate patterns of gene expression and thereby contribute to the complex processes of neural and behavioral adaptation.

A form of perforant path LTP can occur without ERK1/2 phosphorylation or immediate early gene induction

Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that in mice, perforant path LTP can be induced using a standard protocol (repeated trains at 250 Hz), without accompanying increases in immunostaining for p-ERK1/2 or increased in expression of representative IEGs (Arc and c-fos). Signaling pathways capable of inducing ERK phosphorylation and IEG transcription are intact in mice because ERK phosphorylation differs strikingly in awake versus anesthetized mice, and IEG expression is strongly induced by electroconvulsive seizures. In pursuing the reasons for the lack of induction with LTP, we found that in rats, one of the stimulation paradigms used to induce perforant path LTP (trains at 250 Hz) also does not activate MAP kinase or induce IEG expression, despite the fact that the LTP induced by 250 Hz stimulation requires NMDA receptor activation and persists for hours. These findings indicate that there are different forms of perforant path LTP, one of which does not require MAP kinase activation or IEG induction. Moreover, these data demonstrate that different LTP induction paradigms do not have identical molecular consequences, which may account for certain discrepancies between previous studies.

Cheering Up with VEGF

Although the molecular mechanisms of antidepressant action remain unclear, one hypothesis suggests that stimulation of growth factor signaling and of adult neurogenesis in the hippocampus may be implicated in their effects. Warner-Schmidt and Duman investigated the effects of different classes of antidepressants on hippocampal expression of the neurotrophic and pro-angiogenic factor VEGF (vascular endothelial growth factor), which their research group had previously shown to be enhanced by electroconvulsive seizure (ECS) treatment. The abundance of VEGF mRNA increased in the hippocampal granule cell layer of rats treated for 14 days with fluoxetine (a serotonin reuptake inhibitor) or desipramine (a norepinephrine reuptake inhibitor), as did the abundance of VEGF in hippocampal homogenates. Pharmacological blockade of the VEGF receptor Flk-1 inhibited the increase in cell proliferation in the hippocampal subgranular zone (SGZ) produced by ECS or chronic exposure to fluoxetine or desipramine, whereas intracerebroventricular delivery of a VEGF isoform stimulated SGZ cell proliferation. Furthermore, pharmacological blockade of Flk-1 inhibited the effects of desipramine on rat behavioral responses in chronic and subchronic models of antidepressant treatment, whereas VEGF had an antidepressant-like effect. Thus, the authors conclude that VEGF plays a key role in mediating both behavioral effects of several classes of antidepressants and their effects on SGZ cell proliferation. Noting that antidepressants promoted the proliferation of hippocampal endothelial cells as well as hippocampal neurogenesis, the authors speculated that this could play a role in the treatment of certain forms of depression that are associated with vascular abnormalities. J. L. Warner-Schmidt, R. S. Duman, VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc. Natl. Acad. Sci. U.S.A. 104 , 4647-4652 (2007). [Abstract] [Full Text]

Electroconvulsive Seizures Stimulate Glial Proliferation and Reduce Expression of Sprouty2 within the Prefrontal Cortex of Rats

Reductions in cell number are found within the medial prefrontal cortex (PFC) in major depression and bipolar disorder, conditions for which electroconvulsive therapy (ECT) is a highly effective treatment. We investigated whether electroconvulsive seizure (ECS) in rats stimulates cellular proliferation in the PFC immediately and four weeks after the treatments. In parallel, we examined if ECS also alters the expression of Sprouty2 (SPRY2), an inhibitor of cell proliferation. Sprague-Dawley rats received 10 days of ECS treatments and bromodeoxyuridine (BrdU) injections. After a four week survival period, we estimated the density and number of BrdU-, proliferating cell nuclear antigen (PCNA)-, and SPRY2-immunoreactive cells in the medial (infralimbic) PFC (ILPFC). We also determined the percentage of BrdU-labeled cells that were immunoreactive for markers specific to oligodendrocytes, astrocytes, endothelial cells and neurons. ECS dramatically enhanced the proliferation of new cells in the infralimbic PFC, and this effect persisted four weeks following the treatments. The percentage of new cells expressing oligodendrocyte precursor cell markers increased slightly following ECS. In contrast, ECS dramatically reduced the number of cells expressing SPRY2. ECS stimulates long-lasting increases in glial proliferation within the ILPFC. ECS also decreases SPRY2 expression in the same region, an effect that might contribute to increased glial proliferation.