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Review : Stress, Antidepressant Treatments, and Neurotrophic Factors: Molecular and Cellular Mechanisms Ronald S. Duman, Vidita A. Vaidya, Masashi Nibuya, Shigeru Morinobu and Laura Rydelek Fitzgerald Neuroscientist 1995 1: 351 DOI: 10.1177/107385849500100607

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 Stress, Antidepressant Treatments, and Neurotrophic Factors: Molecular and Cellular Mechanisms

RONALD S. DUMAN, VIDITA A. VAIDYA, MASASHI NIBUYA, SHIGERU MORINOBU, and LAURA RYDELEK FITZGERALD Laboratory of Molecular Psychiatry Departments of Psychiatry and Pharmacology Yale University School of Medicine Connecticut Mental Health Center New Haven, Connecticut

Repeated stress or an excess of glucocorticoids can exacerbate neuronal damage in response to insults and, in severe cases, can lead to neuronal atrophy and death. These effects are thought to be related to the actions of stress and glucocorticoids on glutamate function, neuronal metabolism, and the generation of cytotoxic free radicals. Recent studies demonstrate that the regulation of neurotrophic factors may contribute to the actions of stress on neuronal function. Acute or chronic stress decreases the expression of brain derived neurotrophic factor, the most abundant neurotrophin in the brain, in specific regions of the hippocampus, and other forebrain regions. In addition, chronic stress increases the expression of neurotrophin-3 in certain regions of the hippocampus and may, thereby, help to protect these regions from the neurotoxic effects of chronic stress. The deleterious effects of stress may contribute to psychiatric illnesses, such as depression, that can be precipitated or worsened by stress and that are often characterized by hypercortisolism. Electroconvulsive seizure therapy, as well as antidepressant drugs, increase the expression of brain derived neurotrophic factor and its receptor, trkB, in the brain, demonstrating that neurotrophins are a target of antidepressant treatments. These findings outline a role of neurotrophic factors in the etiology and treatment of certain psychiatric illnesses. The Neuroscientist 1:351-360, 1995 KEY WORDS Brain derived neurotrophic factor, Glutamate, Hippocampus, Electroconvulsive seizure, Cell survival, Atrophy

Exposure to stress results in the activation of several stress and adrenal-glucocorticoids on neuronal sur- neurotransmitter pathways (e.g., norepinephrine, se- vival and function and the potential role of neuro- rotonin, dopamine, and glutamate) and neuroendocrine trophic factors in these actions. In addition, the influ- systems, most notably the hypothalamic-pituitary-ad- ence of neurotrophic factors on serotonin and renal axis, which are designed to prepare an animal for norepinephrine, two neurotransmitter systems in- fight or flight responses. However, severe, traumatic volved in the manifestation and treatment of depres- stress or repeated exposure to stress can result in long- sion and other affective illnesses, and the role of neu- term deleterious effects, including even cell atrophy rotrophic factors in the actions of antidepressant and death, which result in behavioral abnormalities. treatments will be discussed. For example, stress is thought to precipitate or exacerbate several psychiatric illnesses, including depres- Influence of Stress and Glucocorticoids on Neuronal Survival and Growth sion, posttraumatic stress disorder, and schizophrenia. Advances in basic research demonstrate that many of The neurochemical and morphological effects of the deleterious effects of stress on neuronal systems stress and high levels of adrenal-glucocorticoids have may result from complex interactions between neuro- been best characterized in the subfields of the hip- transmitters, hormones, and neurotrophins at the cel- pocampus. In certain subfields, the neurons are vul- lular level. This review will discuss the influence of nerable to stress and excess glucocorticoids and cell survival may be decreased. In other subfields, the neurons are more resistant to stress and glucocorti- Dr. Duman’s research is supported by USPHS grants MH45481 coids and their survival is dependent on the presence and 2 PO1 MH25642 and by a Veterans Administration National Cen- of glucocorticoids. This work and the possible mech- ter Grant for PTSD, VA Hospital in West Haven, Connecticut. anisms the actions of stress and Address reprint requests to: Ronald S. Duman, Connecticut Men- underlying glucocor- tal Health Center, 34 Park Street, New Haven, CT 06508. ticoids are briefly reviewed ( 1-4).

Volume 1, Number 6, 1995 351 Copyright @ 1995 by Williams & Wilkins ISSN 1073-8584

Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 Stress-induced Atrophy and Survival of it is possible that similar effects occur on select popu- Hippocampal Neurons lations of neurons throughout the brain. The hippocampus, due to high levels of both type I and Although stress and high levels of adrenal-glucocor- II glucocorticoid receptors, is one of the primary targets ticoids lead to neuronal atrophy of CA3 neurons, the of stress and adrenal steroids in the brain. The effects survival and the function of other neurons in the hip- of stress and adrenal-glucocorticoid treatments are not pocampus are dependent on the presence of glucocor- uniform across the different pyramidal fields and den- ticoids. This effect is most prominent in the dentate gy- tate gyrus (Fig. 1). Severe chronic stress or prolonged rus, where removal of adrenal-glucocorticoids (i.e., exposure to glucocorticoids has been shown to cause adrenalectomy) leads to degeneration and death of gran- cell loss and atrophy of the pyramidal neurons in the ule cells (Fig. 1) (10-13). Long-term adrenalectomy is CA fields, prominently in the CA3 region, whereas the also reported to cause degeneration of CA4 pyramidal granule cells of the dentate gyrus are relatively resistant neurons. Although the exact mechanisms by which glu- to damage by these treatments (5, 6). Dendritic atrophy cocorticoids influence cell survival in the hippocampus of CA3 pyramidal neurons, characterized by the de- are not known, the regulation of cell cycling may be creased number and length of apical dendrites, occurs involved. Granule cells of the dentate gyrus continue to in response to repeated restraint stress or glucocorticoid undergo cell birth and death and thereby maintain a treatment (7, 8). In addition, stress or glucocorticoid relatively static number of cells in the presence of nor- treatments can exacerbate the loss of hippocampal neu- mal physiological levels of glucocorticoids (11, 12). rons in response to other insults, such as excitotoxins, The absence of glucocorticoids enhances cell birth and hypoxia-ischemia, and hypoglycemia (1, 2, 9). The in- death, but cell death proceeds at a faster rate and even- fluence of stress and glucocorticoids on the survival of tually leads to fewer healthy cells. This process can be neurons in other brain regions has not been studied, but reversed by glucocorticoid replacement ( 10-12). These

Fig. 1. Schematic diagram of the hippocampus and the influence of stress on the growth and survival of individual populations of neurons. The CA pyramidal neurons, including CA1 and CA3, and the dentate gyrus granule cells comprise the primary cell groups in the hippocampus. Afferent pathways from the granule cells to CA3 (mossy fiber pathway) and from CA3 to CA1 (Schaffer col- lateral) provide connections within the hippocampus. Exposure to stressful stimuli leads to several effects that may contribute to the atrophy and death of CA3 pyramidal neurons. This includes decreased expression of BDNF in CA3 and CA1 neurons, which would reduce the autocrine and target derived sources of this neurotrophin, respectively. CA3 neurons also lack Ca2+ binding proteins. These characteristics may contribute to increased sensitivity of CA3 neurons to the deleterious effects of stress and glucocorticoids (GCs), including enhanced vulnerability to glutamate neurotoxicity and atrophy of apical dendrites. In contrast, the dentate gyrus granule cells express Ca2+ binding proteins (calbindin-D28 and parvalbumin) and the protective protein, bcl-2, that may make these neurons more resistant to the damaging effects of stress and other neuronal insults. In addition, although stress decreases levels of BDNF in granule cells, chronic, but not acute, stress increases levels of NT-3, which may also contribute to the resistance of these neurons.

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 findings indicate that neuronal survival and function is These findings suggest that the maintenance of neuronal dependent on the appropriate balance of glucocorticoid growth and survival may be dependent, in part, on the levels. presence of serotonin. Cellular and Neurochemical Mechanisms of Alterations of Hippocampal Function and Volume in Stress-induced Atrophy and Death of Neurons Affective Illnesses The neurotoxic effects of stress and excess glucocorti- The hippocampus contributes to feedback inhibition of coids on CA3 pyramidal neurons is thought to involve the hypothalamic-pituitary-adrenal axis via a multisyn- increased activation of glutamatergic pathways (Fig. 1) aptic pathway (20, 21 ). Glucocorticoid-mediated loss of (1). It has been suggested that chronic exposure to stress hippocampal neurons would lead to loss of this inhibi- and glucocorticoids may increase the firing rate of den- tory input: such a cycle would be self-perpetuating and tate granule cells, because adrenalectomy decreases would contribute to enhanced and sustained hypercor- granule cell survival and activity (1). Granule cell tisolism. There is some evidence that this may occur in mossy fibers synapse on CA3 pyramidal neuron apical humans. Young and colleagues (22) demonstrated a loss dendrites, and increased activity of this pathway could of hippocampal feedback inhibition of the hypotha- enhance the release of glutamate at these synapses, lamic-pituitary-adrenal axis in depressed patients. In ad- leading to the reported atrophy of apical dendrites. In dition, Bremner and coworkers (23) reported that hip- support of this hypothesis, stress does not influence py- pocampal volume is decreased in patients with ramidal neuron basal dendrites, which do not receive posttraumatic stress disorder. Although the underlying mossy fiber inputs. CA3 pyramidal neurons also lack nature of these findings is not known, the results are calcium binding proteins, like parvalbumin and calbin- consistent with dysfunction or loss of hippocampal neu- din-D28k, which could compromise the ability of these rons in these stress related disorders. neurons to handle excess calcium (14), and do not ex- Stress and Adrenal Glucocorticoids press the neuroprotective protein, bcl-2 (15). Interest- Regulate the of ingly, neurotrophins are reported to increase the ex- Expression Neurotrophins pression of calbindin in primary hippocampal cultures Expression of neurotrophins contributes to the survival (16, 17). and growth of neurons. The neurotrophin family in- The neurotoxic effects of stress may also involve glu- cludes nerve growth factor (NGF), brain derived neu- cocorticoid-enhancement of glutamate and the loss of rotrophic factor (BDNF), neurotrophin-3 (NT-3), and the homeostatic control of free cytosolic calcium (1, 2, neurotrophin-4/5. These neurotrophins bind to the trk 9). Glucocorticoids are known to increase levels of glu- receptors trkA, trkB, and trkC, which possess protein tamate in response to seizure, to inhibit glutamate reup- tyrosine kinase activity (24-26). Differential expres- take by neurons and glia, to increase intracellular cal- sion of these neurotrophins and their receptors may also cium in response to glutamate, and to increase contribute to the maintenance and survival of certain calcium-dependent proteolysis. The neurotoxic actions neuronal types in response to stress, as well as other of glucocorticoids are also related to glucocorticoid in- types of neuronal insult. Studies demonstrating the reg- hibition of glucose uptake, which compromises the met- ulation of neurotrophins by stress and adrenal gluco- abolic capacity of the neurons. In this compromised corticoids and the potential role of neurotrophins are state, the neurons are unable to counter the effects of discussed below. increased intracellular calcium. Glucocorticoids also influence the generation of free radicals that contribute to Stress Regulates Levels of Neurotrophins in the cellular damage. These findings indicate that any com- Hippocampus bination of stress or excess glucocorticoids, along with The potential role of neurotrophins in the actions of exposure to neuronal insult, could be neurotoxic and stress has been examined by Smith and colleagues (27, lead to atrophy and cell death. 28). Acute restraint (2 h) causes a rapid decrease in The action of glucocorticoid treatments on cell sur- levels of BDNF mRNA in several regions of the hip- vival may involve regulation of other neurotransmitters, pocampus, most prominently in the dentate gyrus and such as serotonin. Atrophy of dendrites and loss of syn- CA3, an effect that has been replicated in our laboratory apses in the hippocampus, as well as other brain (Fig. 2). Repeated chronic stress (7 d) results in a similar regions, in response to serotonin selective neurotoxins degree of BDNF down-regulation in the dentate gyrus is partially reversed by glucocorticoid treatment (18, and CA3 and also decreases levels of BDNF mRNA in 19). This effect of glucocorticoids may occur via in- CAI. In contrast to down-regulation of BDNF, re- creased expression of tryptophan hydroxylase, the rate- peated, but not acute, stress increases the expression of limiting enzyme for serotonin synthesis. In addition, ad- NT-3. Up-regulation of NT-3 mRNA is most prominent ministration of a selective serotonin agonist for the in the dentate gyrus, with smaller effects observed in 5-HT1A receptor partially reverses the loss of synapses CA1 and CA2, and no increase observed in CA3. Stress and dendrites resulting from neurotoxin treatment (19). did not influence the expression of the receptors for

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 sible to rescue these neurons by replacement treatment with BDNF or even NT-3. Conversely, if granule cell resistance is due, in part, to up-regulation of NT-3, then removal of this neurotrophin, using antisense oligonucleotide or knockout strategies, should make these cells more vulnerable to stress and glucocorticoid treatments. In addition to the hippocampus, chronic stress increases the expression of NT-3 in the cell bodies of locus coeruleus, the major noradrenergic cell nucleus in the brain (29). Locus coeruleus neurons are activated by acute and repeated stress, and repeated stress increases the expression of the cAMP signal transduction pathway and the levels of tyrosine hydroxylase, the rate limiting enzyme for catecholamine synthesis (30, 31). These effects of chronic stress are thought to represent a compensatory response to increased demand for norepinephrine synthesis and release in locus coeruleus neurons. Up-regulation of NT-3, which has been shown to increase the survival and function of locus coeruleus neurons (32), could contribute to the increased function of these neurons in response to chronic stress. For example, electrophysiogical studies suggest that mild stress increases the innervation of cerebral cortex by locus coeruleus neurons (33). Conversely, loss of NT- 3 could compromise the ability of locus coeruleus neurons to mount a compensatory response, such as increased expression of tyrosine hydroxylase, required to Fig. 2. Regulation of BDNF by stress and electroconvulsive sei- deal with chronic stress. zure. Acute restraint stress (top pane# decreases the expression of BDNF mRNA in the hippocampus and other brain regions. Role of Glucocorticoids in of Rats were subjected to restraint stress for 2 hours, and BDNF Regulation Stress mRNA was determined by in situ hybridization analysis, using a Neurotrophins by [~5S]-labeled BDNF riboprobe. In contrast, acute ECS (bottom The role of glucocorticoids in the regulation of BDNF pane# increases the expression of BDNF as well as its receptor, and NT-3 by stress has been examined (29). In adre- trkB in the brain. Rats received a ECS stimu- (not shown), single nalectomized with low doses of lus, and levels of BDNF mRNA were determined 2 hours later. rats, supplemented Shown are representative autoradiograms from sham, stress, exogenous glucocorticoids to approximate unstressed and ECS treated rats. hormone levels, the influence of stress on the down- regulation of BDNF and the up-regulation of NT-3 was BDNF or NT-3 and trkB and trkC or the expression of not significantly altered. However, adrenalectomy, in NT-4/5 in these studies. the absence of glucocorticoid supplement, significantly Smith proposed that enhanced expression of NT-3 decreased the expression of NT-3, but not BDNF, in the could replace the loss of BDNF in response to chronic dentate gyrus and CA2 of the hippocampus, suggesting stress and could thereby act in an autocrine fashion to that basal expression of NT-3 is dependent on the pres- help protect those neurons expressing NT-3 (Fig. 1). ence of adrenal glucocorticoids. To further examine the This would be consistent with the findings discussed role of glucocorticoids, rats were administered high above, that dentate gyrus granule cells are most resistant doses of glucocorticoids that approximate levels ob- to the neurotoxic actions of stress and glucocorticoids. served during stress. Acute glucocorticoid treatment (2 In addition, loss of autocrine and target derived BDNF h) did not produce a rapid decrease in the levels of could contribute to the sensitivity of CA3 neurons to BDNF, like that observed after acute restraint stress. chronic stress (Fig. 1). The replacement actions of NT- Repeated treatment (2 to 14 d) decreased the levels of 3 in the face of decreased levels of BDNF could occur BDNF, but this effect was very small relative to that via binding of NT-3 to its high affinity receptor, trkC, observed after acute or chronic stress. Expression of or via binding, albeit with lower affinity, to the trkB NT-3 was not influenced by either acute or repeated receptor. However, the role of BDNF and NT-3 in the glucocorticoid treatment. The results indicate that ex- atrophy and resistance of CA3 pyramidal neurons and cess glucocorticoid levels can not fully explain the reg- dentate gyrus granule cells, respectively, remains to be ulation of BDNF and NT-3 observed during stress, but determined. If decreased expression of BDNF contrib- that adrenal steroids may have a modulatory effect on utes to the atrophy of CA3 neurons, it should be pos- neurotrophin expression (34, 35). Another possibility is

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 that decreased expression of BDNF is mediated by other reported to increase BDNF expression in hippocampal factors (e.g., neuropeptides, cytokines, or interleukins) primary cultures (40) and to mediate, in part, the in- that are released by stress (Fig. 3). duction of BDNF in response to seizures (41), suggesting that this neurotransmitter does not mediate the Role of Neuronal in the of Activity Regulation down-regulation of BDNF in response to stress. Neurotrophins by Stress and of Regulation of neurotrophin expression by stress may be Stress, Neurotrophins, Impairment Memory mediated by the level of neuronal activity and activation One of the consequences of stress is inhibition of short- of stimulatory and/or inhibitory neurotransmitter sys- term memory and cognitive functioning ( 1-4). Given tems (Fig. 3). Expression of BDNF is reported to be the role of the hippocampus in memory and cognition, increased by neuronal activity and by several different it is possible that down-regulation of BDNF by stress neurotransmitter systems (25). For example, activation could contribute to impaired memory and cognition. of glutamate receptors increases the expression of This possibility has been examined with an established BDNF and NGF in the hippocampus, cerebral cortex, cellular model of memory, long-term potentiation, and and other brain regions (36, 37). It is conceivable that animal models of memory and cognition. In long-term stress regulates the expression of BDNF by decreasing potentiation, a brief stimulation of one of the primary stimulatory glutamatergic input. However, as discussed afferent pathways in the hippocampus produces an in- above, increased glutamate neurotoxicity is one hy- crease in the excitatory potential of the postsynaptic pothesis put forth to explain the atrophy observed in cells, usually CA1 or CA3 pyramidal neurons. Long- response to stress and glucocorticoid treatments. In ad- term potentiation leads to an increase in the levels of dition, stress is reported to increase the levels of glu- BDNF (42). Because stress is reported to inhibit long- tamate in the hippocampus, although this effect is sig- term potentiation (43), it is possible that stress-induced nificantly smaller than that observed in other brain down-regulation of BDNF is involved in the loss of a regions (38). Taken together, the observations that potentiated response. In vivo studies demonstrate that stress increases glutamate but decreases expression of expression of BDNF is associated with improved spatial BDNF appear to be contradictory. However, it is pos- memory in animals (44). In addition, cell death in aged sible that stress selectively activates glutamate path- and glucocorticoid-treated rats is correlated with im- ways in specific subfields or neuronal subtypes in the pairment of cognitive performance (45). hippocampus or that the glutamate increase is too small Treatments the to stimulate BDNF expression. This possibility is sup- Antidepressant Regulate of and Their ported by the reports that stress has little or no effect Expression Neurotrophins on the expression of c fos in the hippocampus, which Receptors would be expected if the levels of glutamate were sig- The significant effects of stress and glucocorticoid nificantly increased (39). By contrast, stress signifi- treatments on dendritic atrophy and neuronal survival cantly increases the expression of c-fos in the frontal could also play a role in the pathophysiology and cortex, a brain region where the elevation of extracel- treatment of psychiatric disorders, such as depres- lular glutamate is several-fold greater relative to the hip- sion, that are influenced by stress and often charac- pocampus and where there is no down-regulation of terized by hypercortisolism. Moreover, the finding BDNF in response to stress. that stress decreases the expression of BDNF in sev- Another possibility is that stress inhibits neuronal ac- eral forebrain areas suggests that regulation of neu- tivity via the activation of the inhibitory neurotransmit- rotrophins could contribute to the effects of stress on ter pathways (Fig. 3). For example, blockade of GABA, neuronal maintenance and survival. The ability of the major inhibitory neurotransmitter in the brain, in- neurotrophins to influence the survival and function creases the expression of BDNF (37), and administra- of neurotransmitter systems that are involved in de- tion of diazepam, a benzodiazepine that augments pression (i.e., serotonin and norepinephrine) also sug- GABAergic function, completely blocks kainic acid in- gests that neurotrophins could play a role in the man- duction of BDNF in the hippocampus (36). Stress could ifestation and treatment of such disorders. Recent decrease neuronal activity via activation of inhibitory studies provide direct evidence for this possibility: GABAergic pathways and thereby decrease the expres- Neurotrophins have antidepressant effects in behav- sion of BDNF. This possibility requires additional test- ioral models of depression, and antidepressant treat- ing ; for example, if this is true, GABA antagonists ments influence the expression of neurotrophins. should selectively block the down-regulation of BDNF Enhance Monoamine Neuronal in response to stress. Neurotrophins Stress also increases levels of norepinephrine in the Survival and Function hippocampus and other brain regions (31), and it is pos- Many antidepressant drug treatments acutely increase sible that this monoamine exerts a modulatory effect on the synaptic levels of norepinephrine and serotonin by neurotrophin expression. However, norepinephrine is blocking their reuptake or metabolism (46, 47). How-

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 Fig. 3. Schematic diagram demonstrating the pathways for regulation of neurotrophins by stress, seizures (e.g., ECS), and antidepressant treatments. Acute or chronic stress decreases levels of BDNF in the hippocampus, but the mechanisms underlying this decrease are not known. Glucocorticoid treatments contnbute to the loss of Ca2+ homeostasis, inhibit glucose uptake, and influence the generation of free radicals but cannot fully explain the decrease in levels of BDNF. Stress may influence the expression of BDNF via regulation of other neurotransmitters, such as the inhibitory neurotransmitter, GABA. Depolarization and increased intracellular Ca2+ medi- ates the induction of BDNF, probably via the activation of Ca2+/calmodulin kinase (CAMK) and phosphorylation of CREB (cAMP response element binding protein). Actmation of GABAA receptors and hyperpolarization of neurons could lead to decreased levels of intracellular Ca2+ and inhibition of BDNF expression. Another possibility is that stress activates some unknown factor(s) that decreases the expression of BDNF via the Ca2+ pathway or via another intracellular pathway and transcription factor. Seizures and mild neuronal insults increase the expression of BDNF and trkB via activation of voltage-sensitive Ca2+ channels (VSCC) and glutamate-gated ionic channels, including glutamate (GLU-R) and NMDA receptors: activation of GLU-R depolanzes neurons via influx of Na+ and allows for activation of NMDA receptors that gate Ca2+ and Na+. Activation of VSCC and NMDA channels increases intracellular Ca2+ that activates the CAMK-CREB pathway leading to expression of BDNF. Under normal conditions, Ca2+ homeostasis is maintained by Ca2+ binding proteins (CBP) and by Ca2+ efflux via an ATP-dependent pump and a Na+/Ca2+ exchanger. Antidepressant treatments increase expression of BDNF and trkB, probably by increasing levels of norepinephrine (NE) and serotonin (5-H~. NE and 5-HT may increase BDNF via activation of receptors that stimulate the cAMP system (e.g., 01-adrenergic [,B1AR] and 5-HT4,6,7, respectively]. Al- ternatively, this may occur via receptors that influence Ca2+ kinases (e.g., «,-adrenergic and 5-HT2, not shown). Increased expression of BDNF may contribute to the ability of mild insults and, possibly, antidepressant treatments to protect neurons from stress and neurotoxic insults. ever, the therapeutic action of these treatments is de- NT-3 and BDNF have been reported to influence nor- pendent on chronic treatment (several weeks), suggest- epinephrine and serotonin neurons. The implantation of ing that more long-term adaptations to the acute fibroblasts that express NT-3, but not other neurotro- elevation of these monoamines is required. Recent stud- phins, prevents the degeneration of locus coeruleus neu- ies demonstrate that neurotrophins selectively increase rons in response to the neurotoxin, 6-hydroxydopamine the function of norepinephrine and serotonin neurons (48). NT-3 or NT-4, but not BDNF or NGF, are reported and protect these neurons from neurotoxic damage in to increase significantly the survival of embryonic locus adult animals. Thus, decreased expression of neurotro- coeruleus neurons in culture (32). Chronic infusion of phins could contribute to the loss of monoamine func- BDNF into the midbrain increases the level of serotonin tion and the exacerbation of depression, whereas in- and its turnover in periaqueductal grey, dorsal, and me- creased expression of neurotrophins could contribute to dian raphe, raphe Magus, and raphe pallidus (49). Local the therapeutic action of antidepressants via enhanced infusion of BDNF into the cerebral cortex increases the function of norepinephrine and serotonin neurotrans- density of serotonin immunostaining and protects se- mission. rotonin neurons from neurotoxin damage (50). Taken

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 together, the results demonstrate that BDNF and NT-3 (Fig. 2) (41, 54). In addition, repeated ECS treatment, increase the growth and survival of norepinephrine and for the time required to treat depression, enhances the serotonin neurons. induction of BDNF and trkB in response to acute ECS The neurotrophins also increase the survival and in the frontal cortex and prolongs the expression of function of other neurotransmitter and neuropeptide BDNF and trkB in the hippocampus. The enhanced in- systems, particularly dopamine and neuropeptide Y, duction and prolonged expression of BDNF and trkB which have been implicated in the pathophysiology and observed after chronic treatment may increase neuronal treatment of depression (25). BDNF, NT-3, and NT-4/ growth (e.g., by increasing neurite formation) that may 5 support the survival and development of mesence- contribute to the therapeutic action of this treatment. phalic dopamine neurons and increase the function of Such effects may be dependent on the enhanced and mature dopamine neurons in adult rats. BDNF enhances prolonged expression of BDNF, as reported in cultured the expression of neuropeptide y in cultured cortical cells (55). This could explain the apparent discrepancy neurons. Regulation of these and still other neurotrans- between the acute induction of BDNF and the thera- mitter and neuropeptide systems could contribute to a peutic time course of ECS treatment. role for neurotrophins in the pathophysiology and treat- The influence of antidepressant drug treatments on ment of psychiatric illnesses. the expression of BDNF and trkB has also been examined. Chronic (21 d), but not acute (1 d), treatment Exhibit Effects in Neurotrophins Antidepressant with tranylcypromine (21 d), a monoamine oxidase in- Behavioral Models hibitor antidepressant, significantly increases the ex- Enhancement of monoamine function by neurotrophins pression of BDNF mRNA in the frontal cortex and suggests that these treatments could represent an alter- hippocampus (41, 54). In addition, the chronic admin- nate mechanism to influence behaviors mediated by istration of sertraline or desipramine, selective serotonin norepinephrine and serotonin, particularly behavioral and norepinephrine reuptake inhibitor antidepressants, models of depression (51). To examine this possibility, respectively, tends to increase the levels of BDNF and the influence of chronic BDNF infusion into the mid- to increase significantly the levels of trkB in the hip- brain (near the periaqueductal gray and dorsal raphe) pocampus (54). These findings demonstrate that three on the forced swim and learned helplessness paradigms different classes of antidepressant treatments, as well as was examined. These paradigms have been reported to ECS treatment, increase the expression of BDNF and/ have validity in predicting drugs with antidepressant ac- or trkB in the brain, suggesting that this neurotrophin tivity. In the forced swim test, infusion of BDNF de- system may be a common target of antidepressant treat- creased immobility time by approximately 70%, and, in ments (Fig. 3). the learned helplessness paradigm, BDNF improved the Influence of Treatments on Cell impairment in the number and latency of attempted es- Antidepressant capes to a level comparable to that of control animals. Atrophy and Survival These effects appear to be specific, as BDNF treatment Antidepressant regulation of neurotrophins could re- did not significantly influence locomotor activity. The verse the effects of stress on neurotrophin expression results provide additional support that neurotrophins in- and lead to reversal of the stress-induced atrophy of fluence the neurotransmitter systems involved in de- hippocampal neurons. ECS treatment, 2 hours after the pression. initiation of stress, completely reverses the down-regulation of BDNF mRNA in the hippocampus (Mori- Regulation of Neurotrophins by Antidepressant nobu et al., unpublished observations). In addition, ad- Treatments ministration of a single dose of tranylcypromine or Electroconvulsive seizure (ECS) therapy is the most ef- imipramine, a nonselective serotonin and norepineph- fective and rapidly acting treatment for depression and rine reuptake inhibitor antidepressant, after stress par- bipolar disorder and is often the last line of treatment tially blocks the down-regulation of BDNF. The pos- for patients who are not responsive to available drug sibility that these effects of antidepressants influence the therapies. Seizures induced by electrical stimulation of survival and growth of neurons is supported by a report the hippocampus or pharmacological treatments in- that the coadministration of tianeptine, an atypical an- crease the expression of NGF and BDNF and their re- tidepressant, blocks the stress-induced atrophy of CA3 ceptors in the brain (52, 53). These findings indicate pyramidal neurons (55). that ECS, and possibly other antidepressant drug treat- Seizures and increased neuronal activity increase cell ments, regulate the expression of neurotrophins. This survival and neurite outgrowth, providing additional ev- possibility has been examined by determining the influ- idence that ECS (and possibly antidepressant drugs) ence of ECS and antidepressant drug treatments on the may have similar effects (26, 55). Activation of voltage expression of neurotrophins and their receptors. sensitive Ca2+ channels appears to be an important in- Acute ECS produces a transient induction of BDNF itiating event for increasing neuronal survival (55). In- and trkB mRNA in the hippocampus and cerebral cortex terestingly, activation of voltage sensitive Ca2+ chan-

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 nels results in a prolonged induction of BDNF (Fig. 3), for CREB in ECS induction of BDNF has been dem- similar to that observed after chronic ECS, which is onstrated using antisense oligonucleotides to decrease required for increased neuronal survival (55). In vivo expression of CREB in the hippocampus (54). Local studies have demonstrated that seizures increase neurite infusion of CREB antisense, but not sense, oligonu- sprouting, particularly in mossy fibers from dentate gy- cleotide into the dorsal hippocampus decreases the basal rus granule cells (26); seizures increase the expression levels of BDNF and blocks the induction of BDNF in of BDNF and trkB in these cells, and BDNF treatment response to ECS (Fig. 4). This effect is time dependent increases axonal sprouting of cultured dentate gyrus and reversible, indicating that CREB antisense treat- granule cells (57). It is notable, as alluded to earlier, ment does not decrease BDNF expression by damaging that the induction of BDNF in response to seizures (36, the neurons. 37) parallels the sensitivity of hippocampal neurons to A role for CREB and the cAMP system in the ex- the neurotoxic effects of stress and glucocorticoid treat- pression of BDNF and trkB by antidepressant treatments : Induction of BDNF is lowest in CA3, where ments is further supported by previous studies (47). An- stress- or glucocorticoid-induced atrophy is most prom- tidepressant treatments increase synaptic levels of inent. norepinephrine and serotonin that activate receptors Focal sprouting, like that induced by stimulating dis- (i.e., /3t-adrenergic and 5-HT4,6,7’ respectively) coupled crete brain regions during kindling or that produced by to the cAMP system. In addition, other receptors (e.g., recurrent epileptic seizures, may underlie increased sei- a,-adrenergic or 5-HT2) may be capable of activating zure sensitivity in the affected brain locus. ECS may calcium kinases. Chronic antidepressant treatments are induce a broader effect on neuronal growth throughout reported to result in translocation of cAMP-dependent the brain, not just within a specific brain locus, which may have a neuroprotective effect. For example, seizure pretreatment reduces kainic acid-induced cell damage in the hippocampus and piriform cortex (58). One mechanism by which seizures and prolonged BDNF induction may protect neurons is by increasing the expression of calbindin (20, 21), a Ca2+ binding protein that may buffer excess intracellular Ca2+. Another possibility is that neurotrophins protect neurons by reduc- ing oxidative stress (25). In addition, antidepressant treatments, particularly those that increase levels of serotonin, could enhance neurite outgrowth or exhibit neuroprotective effects via regulation of the trophic factor S 100 (23). Based on these findings, it is likely that repeated ECS treatment increases neurite outgrowth and cell survival in the hippocampus and other brain regions. The influence of ECS and other antidepressant treatments on neuronal sprouting and the relevance of sprouting and cell survival to the actions of antidepressant treatments remain to be determined. Intracellular Pathways Governing the Expression of BDNF Activation of glutamate receptors and voltage-sensitive Ca2+ channels would lead to Ca2+ entry and activation of Ca2+/calmodulin-dependent protein kinase, which could induce BDNF expression via regulation of transcription factors (Fig. 3). One possible transcription fac- 4. CREB antisense oligonucleotide decreases the expres- tor is AMP element Fig. cyclic response binding protein sion of BDNF. CREB antisense (AS) or sense (S) oligonucleo- (CREB), which is activated by Ca2+/calmodulin-depen- tides were infused into the hippocampus (arrows) mark the site dent protein kinase as well as by cyclic AMP-dependent of infusion). Twenty-four hours later, the level of BDNF mRNA protein kinase. In support of this possibility, induction was determined after sham or ECS (2 h) treatment by in situ hybridization. CREB antisense, but not sense, oligonucleotide de- of BDNF in response to and activation of glutamate creased basal and ECS induction of BDNF in the area surround- Ca2+ channels has been voltage-sensitive temporally ing the infusion site. Infusion of CREB antisense, but not sense, correlated with phosphorylation of CREB in primary oligonucleotide decreases the expression of CREB immunohis- cultures of the cerebral cortex (55). Moreover, a role tochemistry (not shown).

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Downloaded from nro.sagepub.com at HOMI BHABHA CENT SCI EDUC on January 31, 2013 protein kinase from the cytosol to the nucleus (59). 9. Stein-Behrens B, Mattson MP, Chang I, Yeh M, Sapolsky R. Stress exacerbates neuron loss and in the These that the cAMP cascade and ex- cytoskeletal pathology findings suggest hippocampus. J Neurosci 1994;14:5373-5380. pression of BDNF and trkB may be a common target 10. Sloviter RS, Valiquette G, Abrams GM, et al. Selective loss of of different classes of antidepressant treatments (Fig. 3). hippocampal granule cells in the mature rat brain after adrenalectomy. Science 1989;243:535-538. Summary and Conclusions 11. Gould E, Woolley CS, Camerson HA, Daniels DC, McEwen BS. Adrenal steroids regulate postnatal development of the rat dentate The studies discussed outline a fraction of the only gyrus: I. Effects of glucocorticoids on cell death. 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