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Depressed Neuroplasticity in Major Depressive Disorder?
EDITORIAL
Depressed Neuroplasticity in Major Depressive Disorder? Since its discovery in the hippocampus of anesthetized rabbit more then 30 years ago (Bliss et al. 2003), long-term potentiation (LTP) of glutamatergic synaptic transmission has become a synonym for the brain’s capacity to reorganize its neuronal networks and store information. Long-term potentiation and its counterpart, long-term depression (LTD), are present in virtually every brain region and occur across species, including humans (Bliss et al. 2003; Cooke and Bliss 2006; Malenka and Bear 2004; Massey and Bashir 2007). Their relevance to memory and behavior has been demonstrated by studies documenting altered synaptic plasticity in several animal models of disease, including major depressive disorder (MDD), schizophrenia, addictive disorders, and Alzheimer’s disease (Gisabella et al. 2005; Kim et al. 2006; Nestler 2001; Rowan et al. 2003). In parallel, the theory that psychiatric disorders are in part disorders of network connectivity and plasticity also has gained attention (Castren 2005; Cooke and Bliss 2006; Mayberg 2007; Spedding et al. 2003). This progress has given rise to the development of non-invasive means for assessing processes that resemble LTP as an avenue for understanding alterations in neuroplasticity that might provide insights into the neurobiology of psychiatric disorders and that might be themselves targets for therapeutic inventions in these disorders. Normann et al (pages 373–380, in this issue) report the first use of a non-invasive means of assessing the cortical plasticity in patients with MDD. Earlier work indicated that in healthy humans (Teyler et al. 2005), as in rodents (Frenkel et al. 2006), repeated presentation of visual checkerboards at high frequency leads to a long-lasting enhancement in the N1b component of the visual evoked response potentials (ERPs) that might reflect a form of sensory LTP. Normann et al. demonstrate that potentiation of the visual evoked potential (VEP) in MDD patients is reduced relative to normal control subjects. In normal control subjects, the repetitive visual stimulation augmented two early components of VEP (P1 and N1) for at least 30 min. In the patient group, the N1 potentiation was not seen. These results resemble the effects of chronic stress, where LTP is diminished and LTD is enhanced (Foy et al. 1987; Holderbach et al. 2007). Thus, these findings might be consistent with a contribution of stress response to the neurobiology of MDD. As the processes that initiate LTD and LTP are distinguished by the frequency of excitatory input, future research will be needed to determine whether the current findings represent a global reduction in neuroplasticity or a shift in cortical neuroplasticity from potentiation to depression (Coussens and Teyler 1996). Also, it is possible that the finding of reduced LTP in MDD does not apply throughout the brain. For example, the fact that exposure to predator stress might attenuate hippocampal LTP and enhance amygdala LTP (Vouimba et al. 2006) indicates that although exposure to predator stress blocked the hippocampal LTP it enhanced the amygdala LTP. Regional differences could be important, because mood disturbances are properties of distributed networks that seem to involve regions including the subgenual cingulate, prefrontal cortex, hypothalamus, and brain stem (Mayberg 2007). Antidepressant medication treatment of patients in this study 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2007.07.008
might complicate the inferences that might be drawn with regard to neuroplasticity deficits associated with MDD. Rather than discontinuing antidepressant medications in severely depressed patients, Normann et al. exposed a group of healthy subjects to subchronic administration of a serotonin reuptake inhibiting (SRI) antidepressant administration, and they found evidence that medications increased neuroplasticity in this group. Although these changes in neuroplasticity might reflect downstream consequences of increased synaptic serotonin concentrations, the specific cellular mechanisms underlying these changes remain to be demonstrated. However, it is unclear how antidepressant medications in this study influenced the results. In animals, SRIs reverse the effects of stress on synaptic plasticity in the rat hippocampus (Holderbach et al. 2007) and in the synapses from the hippocampus to the prefrontal cortex (Rocher et al. 2004). However, SRIs also blocked the induction of LTP in the hippocampus of nonstressed rats (Mnie-Filali et al. 2006; Shakesby et al. 2002; Stewart and Reid 2000). These findings raise the possibility that SRI administration attenuated the magnitude of group differences in this study, leading to an underestimation of the true neuroplasticity impairment associated with MDD. Furthermore, the presence of residual neuroplasticity deficits in antidepressant-treated patients highlights a potentially important limitation of the efficacy of SRI treatment of MDD consistent with the results from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial (Trivedi et al. 2006). As a result, LTP deficits might provide a useful tool for evaluating the efficacy of antidepressant treatment strategies that act more directly on glutamatergic neurotransmission (Pittinger et al. 2007). How confident can we be that potentiation of visual ERP is, indeed, a form of experience-dependent synaptic plasticity that resembles LTP/LTD? Earlier work, using repetitive photic or auditory stimulation in humans, has demonstrated that these changes in the sensory ERP are enduring (Teyler et al. 2005), input-specific (Clapp et al. 2005), and can change polarity with different stimulation frequencies (e.g., photic stimulation at high frequency yields potentiation, which depotentiates with lowfrequency stimulation) (Teyler et al. 2005). In rats, the presentation of visual stimuli with a paradigm similar to the current study induced an NMDA glutamate receptor-dependent potentiation of the visual ERP (Clapp et al. 2006; Frenkel et al. 2006), further strengthening the hypothesis that the changes in the sensory ERP are synaptic. Similarly, Normann et al. show that they produce enduring, stimulus-specific potentiation of the evoked response. However, input specificity is usually shown by presenting two stimuli, either of which could evoke LTP when tetanized separately. In the Normann et al. experiment, whether the flash stimulus can induce potentiation was not tested. The method used to produce potentiation also raises some questions. In typical synaptic plasticity experiments, baseline responses are elicited with infrequently applied stimulus (on the order of .03 Hz), and prolonged tetanizing stimulation at much higher frequency (typically 25–100 Hz) elicits LTP, whereas presentation of low-frequency stimuli (usually .5–2 Hz for 15 min) results in LTD. Instead of producing potentiation with a higher-frequency stimulus (19 Hz), the authors produced potentiation of the evoked BIOL PSYCHIATRY 2007;62:371–372 © 2007 Society of Biological Psychiatry
372 BIOL PSYCHIATRY 2007;62:371–372 response with a prolonged low-frequency (2 Hz) stimulus train. One might have expected the 2-Hz stimulus to produce LTD and the higher-frequency tetanus to produce LTP. However, the authors rightly suggest that these unexpected results might be due to the non-linear response characteristics of a multisynaptic intact brain, as opposed to the much more simplified slice preparation. In a study of human sensory LTP, Teyler et al. (2005) obtained good potentiation with a 9-Hz tetanus—a rate unfortunately not included by Normann et al. If the rules of cortical plasticity in the intact human brain are different then those of synaptic plasticity in animals, then it will be important to launch a translational systems neuroscience effort to bridge the preclinical and clinical LTP findings. In summary, this is an important study that demonstrates a connection between alterations of cortical plasticity and depression. Whether and how this is unique or relevant to the pathology of depression and whether this mechanism can be exploited to deliver therapies remains to be investigated. In addition, similar impairment in the cortical plasticity might occur in other psychiatric disorders, because LTP—a generic mechanism for experience-dependent modification of synaptic strengths—is impaired in several animal models of disease. Timothy J. Teyler University of Idaho Idil Cavus Yale University Departments of Psychiatry and Neurosurgery 300 George St. Room 8304 New Haven, CT 06511 Phone/Fax: (203) 737-1865 The authors do not have any conflicts of interest to disclose. Bliss TV, Collingridge GL, Morris RG (2003): Introduction. Long-term potentiation and structure of the issue. Philos Trans R Soc Lond B Biol Sci 358: 607– 611. Castren E (2005): Is mood chemistry? Nat Rev Neurosci 6:241–246. Clapp WC, Eckert MJ, Teyler TJ, Abraham WC (2006): Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex. Neuroreport 17:511–515. Clapp WC, Kirk IJ, Hamm JP, Shepherd D, Teyler TJ (2005): Induction of LTP in the human auditory cortex by sensory stimulation. Eur J Neurosci 22: 1135–1140. Cooke SF, Bliss TV (2006): Plasticity in the human central nervous system. Brain 129:1659 –1673. Coussens CM, Teyler TJ (1996): Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. Synapse 24:97–103.
www.sobp.org/journal
Editorial Foy MR, Stanton ME, Levine S, Thompson RF (1987): Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol 48:138 –149. Frenkel MY, Sawtell NB, Diogo AC, Yoon B, Neve RL, Bear MF (2006): Instructive effect of visual experience in mouse visual cortex. Neuron 51:339 – 349. Gisabella B, Bolshakov VY, Benes FM (2005): Regulation of synaptic plasticity in a schizophrenia model. Proc Natl Acad Sci U S A 102:13301–13306. Holderbach R, Clark K, Moreau JL, Bischofberger J, Normann C (2007): Enhanced long-term synaptic depression in an animal model of depression. Biol Psychiatry 62:92–100. Kim JJ, Song EY, Kosten TA (2006): Stress effects in the hippocampus: Synaptic plasticity and memory. Stress 9:1–11. Malenka RC, Bear MF (2004): LTP and LTD: An embarrassment of riches. Neuron 44:5–21. Massey PV, Bashir ZI (2007): Long-term depression: Multiple forms and implications for brain function. Trends Neurosci 30:176 –184. Mayberg HS (2007): Defining the neural circuitry of depression: Toward a new nosology with therapeutic implications. Biol Psychiatry 61:729 –730. Mnie-Filali O, El Mansari M, Espana A, Sanchez C, Haddjeri N (2006): Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci Lett 395:23–27. Nestler EJ (2001): Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119 –128. Rocher C, Spedding M, Munoz C, Jay TM (2004): Acute stress-induced changes in hippocampal/prefrontal circuits in rats: Effects of antidepressants. Cereb Cortex 14:224 –229. Rowan MJ, Klyubin I, Cullen WK, Anwyl R (2003): Synaptic plasticity in animal models of early Alzheimer’s disease. Philos Trans R Soc Lond B Biol Sci 358:821– 828. Pittinger C, Sanacora G, Krystal JH (2007): The NMDA receptor as a therapeutic target for major depressive disorder. CNS Neurol Disord Drug Targets 6:101–115. Shakesby AC, Anwyl R, Rowan MJ (2002): Overcoming the effects of stress on synaptic plasticity in the intact hippocampus: Rapid actions of serotonergic and antidepressant agents. J Neurosci 22:3638 –3644. Spedding M, Neau I, Harsing L (2003): Brain plasticity and pathology in psychiatric disease: Sites of action for potential therapy. Curr Opin Pharmacol 3:33– 40. Stewart CA, Reid IC (2000): Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology (Berl) 148:217–223. Teyler TJ, Hamm JP, Clapp WC, Johnson BW, Corballis MC, Kirk IJ (2005): Long-term potentiation of human visual evoked responses. Eur J Neurosci 21:2045–2050. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. (2006): Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 163:28 – 40. Vouimba RM, Munoz C, Diamond DM (2006): Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 9:29 – 40.
Depressed Neuroplasticity in Major Depressive Disorder? Since its discovery in the hippocampus of anesthetized rabbit more then 30 years ago (Bliss et al. 2003), long-term potentiation (LTP) of glutamatergic synaptic transmission has become a synonym for the brain’s capacity to reorganize its neuronal networks and store information. Long-term potentiation and its counterpart, long-term depression (LTD), are present in virtually every brain region and occur across species, including humans (Bliss et al. 2003; Cooke and Bliss 2006; Malenka and Bear 2004; Massey and Bashir 2007). Their relevance to memory and behavior has been demonstrated by studies documenting altered synaptic plasticity in several animal models of disease, including major depressive disorder (MDD), schizophrenia, addictive disorders, and Alzheimer’s disease (Gisabella et al. 2005; Kim et al. 2006; Nestler 2001; Rowan et al. 2003). In parallel, the theory that psychiatric disorders are in part disorders of network connectivity and plasticity also has gained attention (Castren 2005; Cooke and Bliss 2006; Mayberg 2007; Spedding et al. 2003). This progress has given rise to the development of non-invasive means for assessing processes that resemble LTP as an avenue for understanding alterations in neuroplasticity that might provide insights into the neurobiology of psychiatric disorders and that might be themselves targets for therapeutic inventions in these disorders. Normann et al (pages 373–380, in this issue) report the first use of a non-invasive means of assessing the cortical plasticity in patients with MDD. Earlier work indicated that in healthy humans (Teyler et al. 2005), as in rodents (Frenkel et al. 2006), repeated presentation of visual checkerboards at high frequency leads to a long-lasting enhancement in the N1b component of the visual evoked response potentials (ERPs) that might reflect a form of sensory LTP. Normann et al. demonstrate that potentiation of the visual evoked potential (VEP) in MDD patients is reduced relative to normal control subjects. In normal control subjects, the repetitive visual stimulation augmented two early components of VEP (P1 and N1) for at least 30 min. In the patient group, the N1 potentiation was not seen. These results resemble the effects of chronic stress, where LTP is diminished and LTD is enhanced (Foy et al. 1987; Holderbach et al. 2007). Thus, these findings might be consistent with a contribution of stress response to the neurobiology of MDD. As the processes that initiate LTD and LTP are distinguished by the frequency of excitatory input, future research will be needed to determine whether the current findings represent a global reduction in neuroplasticity or a shift in cortical neuroplasticity from potentiation to depression (Coussens and Teyler 1996). Also, it is possible that the finding of reduced LTP in MDD does not apply throughout the brain. For example, the fact that exposure to predator stress might attenuate hippocampal LTP and enhance amygdala LTP (Vouimba et al. 2006) indicates that although exposure to predator stress blocked the hippocampal LTP it enhanced the amygdala LTP. Regional differences could be important, because mood disturbances are properties of distributed networks that seem to involve regions including the subgenual cingulate, prefrontal cortex, hypothalamus, and brain stem (Mayberg 2007). Antidepressant medication treatment of patients in this study 0006-3223/07/$32.00 doi:10.1016/j.biopsych.2007.07.008
might complicate the inferences that might be drawn with regard to neuroplasticity deficits associated with MDD. Rather than discontinuing antidepressant medications in severely depressed patients, Normann et al. exposed a group of healthy subjects to subchronic administration of a serotonin reuptake inhibiting (SRI) antidepressant administration, and they found evidence that medications increased neuroplasticity in this group. Although these changes in neuroplasticity might reflect downstream consequences of increased synaptic serotonin concentrations, the specific cellular mechanisms underlying these changes remain to be demonstrated. However, it is unclear how antidepressant medications in this study influenced the results. In animals, SRIs reverse the effects of stress on synaptic plasticity in the rat hippocampus (Holderbach et al. 2007) and in the synapses from the hippocampus to the prefrontal cortex (Rocher et al. 2004). However, SRIs also blocked the induction of LTP in the hippocampus of nonstressed rats (Mnie-Filali et al. 2006; Shakesby et al. 2002; Stewart and Reid 2000). These findings raise the possibility that SRI administration attenuated the magnitude of group differences in this study, leading to an underestimation of the true neuroplasticity impairment associated with MDD. Furthermore, the presence of residual neuroplasticity deficits in antidepressant-treated patients highlights a potentially important limitation of the efficacy of SRI treatment of MDD consistent with the results from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial (Trivedi et al. 2006). As a result, LTP deficits might provide a useful tool for evaluating the efficacy of antidepressant treatment strategies that act more directly on glutamatergic neurotransmission (Pittinger et al. 2007). How confident can we be that potentiation of visual ERP is, indeed, a form of experience-dependent synaptic plasticity that resembles LTP/LTD? Earlier work, using repetitive photic or auditory stimulation in humans, has demonstrated that these changes in the sensory ERP are enduring (Teyler et al. 2005), input-specific (Clapp et al. 2005), and can change polarity with different stimulation frequencies (e.g., photic stimulation at high frequency yields potentiation, which depotentiates with lowfrequency stimulation) (Teyler et al. 2005). In rats, the presentation of visual stimuli with a paradigm similar to the current study induced an NMDA glutamate receptor-dependent potentiation of the visual ERP (Clapp et al. 2006; Frenkel et al. 2006), further strengthening the hypothesis that the changes in the sensory ERP are synaptic. Similarly, Normann et al. show that they produce enduring, stimulus-specific potentiation of the evoked response. However, input specificity is usually shown by presenting two stimuli, either of which could evoke LTP when tetanized separately. In the Normann et al. experiment, whether the flash stimulus can induce potentiation was not tested. The method used to produce potentiation also raises some questions. In typical synaptic plasticity experiments, baseline responses are elicited with infrequently applied stimulus (on the order of .03 Hz), and prolonged tetanizing stimulation at much higher frequency (typically 25–100 Hz) elicits LTP, whereas presentation of low-frequency stimuli (usually .5–2 Hz for 15 min) results in LTD. Instead of producing potentiation with a higher-frequency stimulus (19 Hz), the authors produced potentiation of the evoked BIOL PSYCHIATRY 2007;62:371–372 © 2007 Society of Biological Psychiatry
372 BIOL PSYCHIATRY 2007;62:371–372 response with a prolonged low-frequency (2 Hz) stimulus train. One might have expected the 2-Hz stimulus to produce LTD and the higher-frequency tetanus to produce LTP. However, the authors rightly suggest that these unexpected results might be due to the non-linear response characteristics of a multisynaptic intact brain, as opposed to the much more simplified slice preparation. In a study of human sensory LTP, Teyler et al. (2005) obtained good potentiation with a 9-Hz tetanus—a rate unfortunately not included by Normann et al. If the rules of cortical plasticity in the intact human brain are different then those of synaptic plasticity in animals, then it will be important to launch a translational systems neuroscience effort to bridge the preclinical and clinical LTP findings. In summary, this is an important study that demonstrates a connection between alterations of cortical plasticity and depression. Whether and how this is unique or relevant to the pathology of depression and whether this mechanism can be exploited to deliver therapies remains to be investigated. In addition, similar impairment in the cortical plasticity might occur in other psychiatric disorders, because LTP—a generic mechanism for experience-dependent modification of synaptic strengths—is impaired in several animal models of disease. Timothy J. Teyler University of Idaho Idil Cavus Yale University Departments of Psychiatry and Neurosurgery 300 George St. Room 8304 New Haven, CT 06511 Phone/Fax: (203) 737-1865 The authors do not have any conflicts of interest to disclose. Bliss TV, Collingridge GL, Morris RG (2003): Introduction. Long-term potentiation and structure of the issue. Philos Trans R Soc Lond B Biol Sci 358: 607– 611. Castren E (2005): Is mood chemistry? Nat Rev Neurosci 6:241–246. Clapp WC, Eckert MJ, Teyler TJ, Abraham WC (2006): Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex. Neuroreport 17:511–515. Clapp WC, Kirk IJ, Hamm JP, Shepherd D, Teyler TJ (2005): Induction of LTP in the human auditory cortex by sensory stimulation. Eur J Neurosci 22: 1135–1140. Cooke SF, Bliss TV (2006): Plasticity in the human central nervous system. Brain 129:1659 –1673. Coussens CM, Teyler TJ (1996): Protein kinase and phosphatase activity regulate the form of synaptic plasticity expressed. Synapse 24:97–103.
www.sobp.org/journal
Editorial Foy MR, Stanton ME, Levine S, Thompson RF (1987): Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol 48:138 –149. Frenkel MY, Sawtell NB, Diogo AC, Yoon B, Neve RL, Bear MF (2006): Instructive effect of visual experience in mouse visual cortex. Neuron 51:339 – 349. Gisabella B, Bolshakov VY, Benes FM (2005): Regulation of synaptic plasticity in a schizophrenia model. Proc Natl Acad Sci U S A 102:13301–13306. Holderbach R, Clark K, Moreau JL, Bischofberger J, Normann C (2007): Enhanced long-term synaptic depression in an animal model of depression. Biol Psychiatry 62:92–100. Kim JJ, Song EY, Kosten TA (2006): Stress effects in the hippocampus: Synaptic plasticity and memory. Stress 9:1–11. Malenka RC, Bear MF (2004): LTP and LTD: An embarrassment of riches. Neuron 44:5–21. Massey PV, Bashir ZI (2007): Long-term depression: Multiple forms and implications for brain function. Trends Neurosci 30:176 –184. Mayberg HS (2007): Defining the neural circuitry of depression: Toward a new nosology with therapeutic implications. Biol Psychiatry 61:729 –730. Mnie-Filali O, El Mansari M, Espana A, Sanchez C, Haddjeri N (2006): Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci Lett 395:23–27. Nestler EJ (2001): Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119 –128. Rocher C, Spedding M, Munoz C, Jay TM (2004): Acute stress-induced changes in hippocampal/prefrontal circuits in rats: Effects of antidepressants. Cereb Cortex 14:224 –229. Rowan MJ, Klyubin I, Cullen WK, Anwyl R (2003): Synaptic plasticity in animal models of early Alzheimer’s disease. Philos Trans R Soc Lond B Biol Sci 358:821– 828. Pittinger C, Sanacora G, Krystal JH (2007): The NMDA receptor as a therapeutic target for major depressive disorder. CNS Neurol Disord Drug Targets 6:101–115. Shakesby AC, Anwyl R, Rowan MJ (2002): Overcoming the effects of stress on synaptic plasticity in the intact hippocampus: Rapid actions of serotonergic and antidepressant agents. J Neurosci 22:3638 –3644. Spedding M, Neau I, Harsing L (2003): Brain plasticity and pathology in psychiatric disease: Sites of action for potential therapy. Curr Opin Pharmacol 3:33– 40. Stewart CA, Reid IC (2000): Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology (Berl) 148:217–223. Teyler TJ, Hamm JP, Clapp WC, Johnson BW, Corballis MC, Kirk IJ (2005): Long-term potentiation of human visual evoked responses. Eur J Neurosci 21:2045–2050. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. (2006): Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 163:28 – 40. Vouimba RM, Munoz C, Diamond DM (2006): Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 9:29 – 40.