Schizophrenia Research Forum - A Catalyst for Creative Thinking

Prozac and Plasticity—Antidepressant’s Action an Eye Opener

25 April 2008. Selective serotonin reuptake inhibitors such as fluoxetine (better known as Prozac) have always been a bit of a puzzle. Though they quickly elevate serotonin levels, it can take weeks for these drugs to have a noticeable antidepressant effect. Research from the past decade suggests that these drugs have a much more profound and gradual mode of action, possibly related to increased synthesis of new neurons and new neural connections.

In last week’s Science, researchers led by Jose Maya Vetencourt and Lamberto Maffei at the Institute for Neuroscience, National Research Council, Pisa, Italy, collaborating with Eero Castrén's group at the University of Helsinki, reported that antidepressants do, indeed, induce changes in neuronal connections and that these neural rearrangements are functionally significant. They found that antidepressants can promote restructuring of the mammalian visual cortex, turning an eye with poorly developed neural connections into a well-connected, useful one. Beyond the immediate hope for treating amblyopia, or “lazy eye,” the study offers new insights into the effects of antidepressants and the treatment of mood disorders. Further, because the benefits of the drug depended upon visual stimulation, the study supports a synergistic interplay of the drugs and environmental factors, which might include behavioral or psychotherapy in the case of mood disorders.

These results may be of interest to schizophrenia researchers for several other reasons: at a mechanistic level, Maya Vetencourt and colleagues found that brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA), both molecules of interest for schizophrenia researchers, are involved in the restoration of adult neuronal plasticity.

Visual cortical plasticity—a classic neurobiological model
In young mammals, covering one eye leads to a shift in the neuronal circuitry of the visual cortex to favor the other eye. This trick can even be used to correct visual problems. When one eye is weaker than the other, covering the stronger eye (monocular deprivation) shifts the visual circuitry until visual acuity in the weaker eye is restored. Usually this only works during a time when the circuitry is “plastic” or easily rewired, as in children. In adults, covering the good eye usually has no effect on the weaker one. That situation changes if fluoxetine enters the picture, according to Maya Vetencourt and colleagues.

Using a monocular deprivation (MD) model in rats, the researchers found that visual acuity is restored in adult rats if they are chronically treated with fluoxetine. To measure visual acuity, the researchers relied on evoked electrical activity in the visual cortex. In adult amblyopic rats, uncovering the deprived eye during the last two weeks of chronic fluoxetine treatment resulted in a complete recovery of visual evoked potentials (VEPs) in the corresponding visual cortex of the brain. In contrast, there was no restoration of visual acuity in animals that did not receive the antidepressant. Behavioral testing also revealed the restoration of visual acuity to the deprived eye, and the fluoxetine treatment also restored binocular vision, as judged by the ratio of electrical activity in the right and left visual cortices. “Our findings demonstrate that chronic fluoxetine administration reinstates a juvenile-like form of OD [optical dominance] plasticity in adulthood, which is indicated by a decrease in the response to stimulation of the deprived eye and promotes a complete recovery of visual function in adult amblyopic rats,” write the authors.

Neurotransmitters and neurotrophins
How does this antidepressant have such a dramatic effect on the visual cortex? One possibility is that it relieves some restraint on neural reorganization. For example, it is believed that inhibitory neurons put an end to the plasticity of the visual system during postnatal development. To test if these inhibitory influences may have been quashed by the antidepressant, the researchers measured levels of GABA (the major inhibitory neurotransmitter). They found that baseline levels of GABA were significantly reduced in fluoxetine-treated animals, and that long-term potentiation (LTP), a form of neural plasticity not normally found in the adult visual cortex, was restored. The findings indicate that it is the GABA inhibitory neurons that prevent the adult visual system from undergoing major changes in circuitry. This is supported by the fact that diazepam, a GABA agonist, prevents the reorganization of visual circuitry in response to fluoxetine.

Relief from GABA may not be the only way antidepressants have such a dramatic effect on the visual system. The authors also confirmed that BDNF levels are significantly elevated by fluoxetine and that simply injecting the trophin into the cortex is sufficient to start shifting the circuitry in response to monocular deprivation. This observation also fits with some earlier work from these researchers that showed environmental enrichment (EE) restores visual acuity in amblyopic rats (see Sale et al., 2007)—EE is known to elevate brain BDNF levels (see Adlard et al., 2005). The researchers conclude that the combination of reduced GABA inhibition and increased BDNF expression induced by chronic fluoxetine somehow alters the genes that regulate plasticity, allowing a functional modification of neuronal circuitries. They suggest that this side effect of antidepressant treatment might serve as a means to correct amblyopia in humans.

“Our data also indicate a potential clinical application for antidepressants in neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition,” write the authors. In the case of schizophrenia, however, too little intracortical inhibition may be the case, and deficits in GABA transmission are specifically implicated (see SRF related news story). The relevance of this work for schizophrenia at the molecular level is also worth considering. In addition to GABA dysfunction, there are indications that levels of both BDNF (see Durany et al., 2001) and BDNF-containing neurons are reduced in the brains of people with schizophrenia (see Iritani et al., 2003). However, it is unlikely that the answer will be as simple as boosting BDNF levels in any psychiatric disorder. For example, there are indications that too much BDNF in other areas of the brain may be detrimental to proper brain functions (see SRF related news story).—Tom Fagan.

Reference:
Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, Castren E, Maffei L. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science April 18, 2007;320:385-388. Abstract

Q&A with Eero Castrén. Questions by Schizophrenia Research Forum.

Q: What prompted you to do this study?
A: The clinical effects of antidepressants appear with a delay, and increased neuronal plasticity and alterations in network structure have been suggested to underlie this delay (
Castrén, 2005). However, a direct demonstration that antidepressants would functionally alter neuronal networks has been lacking.

Q: How did you tackle this problem?
A: We used the visual cortex, a classical model structure for developmental plasticity, to examine the effects of fluoxetine on cortical network rearrangements in rats. Our results demonstrate that fluoxetine reactivates the critical period plasticity in the adult visual cortex and facilitates functional recovery of miswired neuronal networks.

Q: Can you give us some background on this model?
A: Plasticity in the visual cortex is high during a critical period of postnatal development, when inputs from the two eyes compete for the innervation of the visual cortex and the functional networks are laid down (Hensch, 2005). If one eye is deprived of vision during the critical period, the inputs of the active open eye occupy the visual cortex and those from the closed eye are withdrawn, leaving the eye poor in vision, a condition known as amblyopia. Opening the eye and patching of the better eye during the critical period allows the weaker eye recovery of its connectivity and visual acuity. In adulthood, after the end of the critical period, plasticity is more restricted and closure of one eye no longer leads to the loss of innervation; conversely, an amblyopic eye not treated with patching of the better eye during the critical period remains poor in vision.

Q: So what was the main finding?
A: We found that peroral fluoxetine treatment for three weeks reopens the critical period plasticity in the adult visual cortex and closure of one eye leads to the shift in the cortical innervation to favor that of the open eye. Furthermore, if an amblyopic eye covered during the critical period is reopened in adulthood, vision improved in the weaker eye to finally equal that of the healthy eye when fluoxetine treatment was combined with covering the better eye.

Q: What is the basis for this renewed plasticity?
A: The enhanced plasticity was associated with increased BDNF expression in the visual cortex, and infusion of BDNF into visual cortex mimicked the effects of fluoxetine. Intracortical inhibition, which is known to regulate critical period plasticity, was reduced and increasing inhibition by intracortical infusion of diazepam blocked the effects of fluoxetine on plasticity. Thus, BDNF signaling and cortical GABAergic networks play a critical role in the mechanisms through which antidepressants facilitate cortical plasticity.

Q: What does this work tell us about the action of antidepressants?
A: These experiments convincingly demonstrate that antidepressants induce plasticity in the visual cortex and facilitate functional rearrangements leading to a recovery of a faulty network miswired due to imbalanced environmental stimuli during the postnatal development.

Q: Does this have any relevance to human conditions?
A: Antidepressants may have similar effects also in the human visual cortex. Normann et al. showed recently that while neuronal plasticity in the visual cortex of depressed patients was reduced, treatment of healthy volunteers with another SSRI, sertraline, enhanced plasticity over that seen in untreated controls (Normann et al., 2007).

It is important to note, however, that fluoxetine did not repair the network on its own; it merely enhanced plasticity to facilitate the ability of environmental cues to guide the rearrangement of the connectivity. Maffei’s lab has previously shown that raising rats in an enriched environment has effects equivalent to those of fluoxetine: an enriched environment enhances plasticity in adult visual cortex and allowed a recovery of an amblyopic eye in adults (Sale et al., 2007).

Q: What about other areas of the cortex, such as those involved in mood regulation. Is it possible that fluoxetine and other antidepressants might have analogous effects there?
A: That remains to be seen. If this was the case, antidepressants, through BDNF signaling, might facilitate the recovery of dysfunctional cortical networks miswired by disruptive early life experiences or perhaps during extended stress. However, in this case, too, beneficial environmental cues, such as rehabilitation or talk therapy, would be required to guide rearranging networks for functional recovery, which is consistent with the observations that antidepressants and psychotherapy together work better than either one alone.

Q: Is there any reason for clinicians to be concerned about the use of antidepressants in schizophrenia, which is pretty common? A prominent body of work in schizophrenia revolves around the idea of GABA hypofunction in prefrontal cortex. If fluoxetine further depresses GABA function, then might not these drugs counteract any psychotherapeutic interventions?
A: For the schizophrenia, it is true that the GABAergic system is implicated; however, this system is multifaceted and complicated. I would be very cautious about rushing into any direct conclusions based on our study. On the contrary, there are decades of clinical experience about using antidepressants in schizophrenics—if something alarming would happen, that would be known by now.

Incidentally, there is an interesting review from the McGuire lab in Lancet (Fusar-Poli et al., 2007) reviewing data that suggest that antidepressant treatment might protect against the first episode of schizophrenia in at-risk people. Whether this has anything to do with the plasticity found in our study remains to be seen. However, it seems to me that it is not useful, and might even be harmful, to strictly label drugs into slots such as "antidepressants" and "antipsychotics," etc. It should be evident already (they are useful for a variety of neuropsychiatric disorders), and further emphasized by our study, that antidepressants do something very different than simply counteracting depression. A fresh look is what is needed.

Comments on News and Primary Papers
Comment by:  Keri Martinowich
Submitted 30 April 2008
Posted 1 May 2008

The recent paper by Vetencourt et al., showing that fluoxetine can restore neuronal plasticity in the adult visual system, has quite obvious and exciting potential applications for the treatment of amblyopia. However, beyond this potential unexpected use for fluoxetine in the clinical treatment of eye disorders, lie implications and new insight into antidepressant mechanisms of actions in mood disorders. It has been speculated for some time that the need for chronic treatment with antidepressants to achieve a therapeutic effect is dependent on changes in neuronal and synaptic plasticity. Time and again, regulation of BDNF has emerged as a candidate underlying various depressive and/or anxiety-like phenotypes, as well as being a possible mediator of the effect of antidepressant/mood-stabilizer drugs. It is now well accepted that beyond its role as a trophic factor during development, BDNF plays a key role in regulating neuronal plasticity in the adult central nervous system.

Clinicians, patients and clinical trials alike attest that antidepressants have strong effects, but the understanding of how exactly they exert their function has remained a mystery despite intense speculation and study. Mechanistic understanding of antidepressant function may provide valuable clues about the functional effects of these drugs, which will likely facilitate our ability to develop treatments with faster therapeutic onset and fewer or less severe side effects by allowing us to precisely target the necessary sites of action.

Reports like the current one are refreshing to the field, reminding us that sometimes, the answers to our questions might be best answered by looking in a different direction rather than focusing and refocusing on the current studies. The sites of action of antidepressant drugs and mood stabilizing therapies are likely to be not just in one place, but in several or even many, interacting circuits within the limbic system of the brain. Teasing apart these circuits and visualizing the effects that antidepressants have on these functional circuits is of course, technically challenging. The comparative simplicity and better understanding of the visual system, makes it an attractive system for the present type of molecular studies. Clearly, biology has made use of redundancy with systems that work well. This biological redundancy may afford us the use of more manageable systems that allow us to observe physiological effects of antidepressants and mood-stabilizing drugs that can be extrapolated to areas of the brain important for regulation of mood and behavior.

View all comments by Keri Martinowich

Comments on Related News


Related News: BDNF In the Nucleus Accumbens—Too Much of a Good Thing?

Comment by:  NN Kudryavtseva
Submitted 23 February 2006
Posted 23 February 2006

Berton and colleagues show very impressive data of molecular studies demonstrating numerous changes of gene expression in brain under repeated social defeats. However, the behavioral or pharmacological data that the authors use to support the development of depression in socially defeated mice may be interpreted otherwise.

The authors used decreases in the level of social communication (they called it avoidance-approach behavior) in defeated losers as parameters of depression. We repeatedly noted in our experiments on the social model of depression induced by social confrontations in mice of the C57BL/6J strain (Kudryavtseva et al., 1991) that even one or two social defeats lead to a decrease of communication in mice. Thus, avoidance behavior cannot be used as a specific parameter of depression; rather, it may represent anxiety. However, our experiments demonstrated that longer experience of defeats over 20-30 days (but not 10 days, as used by Berton et al.) in male mice produces development of a depression-like state (anxious depression): similarities of symptoms, etiological factors (social unavoidable emotional stress, permanent anxiety), sensitivity to chronic antidepressants and anxiolytics (imipramine, tianeptine, citalopram, fluoxetine, buspirone, etc.), as well as brain neurochemistry changes (serotonergic and dopaminergic systems) (Kudryavtseva et al., 1991; for reviews see Kudryavtseva, Avgustinovich, 1998; Avgustinovich et al., 2004).

In our molecular studies, we also demonstrated changes of gene expression in the brains of male mice after daily agonistic interactions. Three experimental groups were compared: the losers with repeated experience of social defeats; winners with repeated aggression accompanied by social victories; and controls (very important—the same strain). In has been shown that MAOA and SERT mRNA levels in the raphe nuclei of the losers were higher than in the controls and winners. TH and DAT gene expression in the ventral tegmental area was higher and κ opioid receptor gene expression was lower in the winners in comparison with the losers and controls (see Filipenko et al., 2001; 2002; Goloshchapov et al., 2005; reviewed in Kudryavtseva et al., 2004). Thus, there are different specific changes in gene expression in different brain areas in male mice with opposite social behaviors—winners and losers.

As for BDNF, there is an emerging body of data suggesting that different mood disorders are associated with changed BDNF. I think that changes of BDNF gene expression in the losers may be nonspecific for depression state. Expression of the BDNF gene in the winners should be investigated to confirm or reject this idea.

Again, Berton et al. (2006) have demonstrated very impressive data. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model) may be used for the study of association between agonistic behavior and gene expression. We called this scientific direction “From behavior to gene” (reviewed in Kudryavtseva et al., 2004), as an addition to the traditional “From gene to behavior.”

References:

Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991 Feb;38(2):315-20. Abstract

Kudryavtseva NN, Avgustinovich DF. (1998) Behavioral and physiological markers of experimental depression induced by social conflicts (DISC). Aggress Behav. 24:271-286.

Filipenko ML, Alekseyenko OV, Beilina AG, Kamynina TP, Kudryavtseva NN. Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience. Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):77-81. Abstract

Filipenko ML, Beilina AG, Alekseyenko OV, Dolgov VV, Kudryavtseva NN. Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice. Neurosci Lett. 2002 Mar 15;321(1-2):25-8. Abstract

Kudryavtseva et al. (2004) Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: From behavior to gene. Genetika, 40(6):732-748.

Avgustinovich DF, Alekseenko OV, Bakshtanovskaia IV, Koriakina LA, Lipina TV, Tenditnik MV, Bondar' NP, Kovalenko IL, Kudriavtseva NN. [Dynamic changes of brain serotonergic and dopaminergic activities during development of anxious depression: experimental study] Usp Fiziol Nauk. 2004 Oct-Dec;35(4):19-40. Review. Russian. Abstract

Goloshchapov AV, Filipenko ML, Bondar NP, Kudryavtseva NN, Van Ree JM. Decrease of kappa-opioid receptor mRNA level in ventral tegmental area of male mice after repeated experience of aggression. Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):290-2. Epub 2005 Jan 6. Abstract

View all comments by NN Kudryavtseva

Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 26 June 2007
Posted 26 June 2007

The evidence is becoming overwhelming that the GABA system disturbances are a critical hallmark of schizophrenia. The data indicate that these processes are present across different brain regions, albeit with some notable differences in the exact genes affected. Synthesizing the observations from the recent scientific reports strongly suggest that the observed GABA system disturbances arise as a result of complex genetic-epigenetic-environmental-adaptational events. While we currently do not understand the nature of these interactions, it is clear that this will become a major focus of translational neuroscience over the next several years, including dissecting the pathophysiology of these events using in vitro and in vivo experimental models.

View all comments by Karoly Mirnics

Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia

Comment by:  Schahram Akbarian
Submitted 26 June 2007
Posted 26 June 2007
  I recommend the Primary Papers

The three papers discussed in the above News article are the most recent to imply dysregulation of the cortical GABAergic system in schizophrenia and related disease. Each paper adds a new twist to the story—molecular changes in the hippocampus of schizophrenia and bipolar subjects show striking differences dependent on layer and subregion (Benes et al), and in prefrontal cortex, there is mounting evidence that changes in the "GABA-transcriptome" affect certain subtypes of inhibitory interneurons (Hashimoto et al). The polymorphisms in the GAD1/GAD67 (GABA synthesis) gene which Straub el al. identified as genetic modifiers for cognitive performance and as schizophrenia risk factors will undoubtedly spur further interest in the field; it will be interesting to find out in future studies whether these genetic variants determine the longitudinal course/outcome of the disease, treatment response etc etc.

View all comments by Schahram Akbarian